Substituted piperidine compound and use thereof

ABSTRACT

Provided is a substituted piperidine compound having an orexin type 2 receptor agonist activity. A compound represented by the formula (I): 
                         
wherein each symbol is as described in the DESCRIPTION, or a salt thereof has an orexin type 2 receptor agonist activity, and is useful as a prophylactic or therapeutic agent for narcolepsy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of U.S. application Ser. No.15/421,702, filed Feb. 1, 2017, which claims priority to JP 2016-019834,filed Feb. 4, 2016.

TECHNICAL FIELD

The present invention relates to a substituted piperidine compound,particularly, a substituted piperidine compound having an orexin type 2receptor agonist activity.

BACKGROUND OF THE INVENTION

Orexin is a neuropeptide specifically produced in particular neuronslocated sparsely in the lateral hypothalamus and its surrounding area,and consists of two subtypes, orexin A and orexin B. Both orexin A andorexin B are endogenous ligands of the orexin receptors, which are Gprotein-coupled receptors mainly present in the brain, and two types ofsubtypes, type 1 and type 2, are known for the orexin receptors(non-patent document 1).

Since orexin-producing neurons (orexin neurons) are localized in thevicinity of the feeding center, and intraventricular administration oforexin peptide results in an increase in food intake, orexin initiallyattracted attention as a neuropeptide having a feeding behavioralregulation. Thereafter, however, it was reported that the cause of dognarcolepsy is genetic variation of orexin type 2 receptor (non-patentdocument 2), and the role of orexin in controlling sleep and wakefulnesshas been also attracted.

From the studies using a transgenic mouse having denatured orexinneurons and a double transgenic mouse obtained by crossing this mousewith orexin overexpressing transgenic mouse, it was clarified thatnarcolepsy-like symptoms that appear by degeneration of orexin neuronsdisappear due to sustained expression of orexin. Similarly, when orexinpeptide was intraventricularly administered to a transgenic mouse havingdenatured orexin neuron, improvement of narcolepsy-like symptoms wasalso observed (non-patent document 3). Studies of orexin type 2 receptorknockout mice have suggested that orexin type 2 receptor is importantfor maintaining arousal (non-patent document 4, non-patent document 5).Such background suggests that orexin type 2 receptor agonists becometherapeutic drugs for narcolepsy or therapeutic drugs for other sleepdisorders exhibiting excessive sleepiness (non-patent document 6).

In addition, it is suggested that a peptidic agonist that selectivelyacts on the orexin type 2 receptor improves obesity due to high fat dietload in mice (non-patent document 7).

In addition, it is suggested that intraventricular administration oforexin peptide shortens the systemic anesthetic time of rat (non-patentdocument 8).

In addition, it is suggested that patients with sleep apnea syndromeshow low orexin A concentration levels in plasma (non-patent document9).

In addition, it is suggested that intraventricular administration oforexin peptide improves memory retention of senescence-accelerated modelmouse (SAMP8) with cognitive dysfunction (non-patent document 10).

In addition, it is suggested that Orexin type 2 receptor agonist will bea therapeutic drug for cardiac failure (patent document 1, non-patentdocument 11).

In addition, it is suggested that the daytime sleepiness of Parkinson'sdisease patients is caused by orexin nerve fallout (non-patent document12).

In addition, it is suggested that orexin regulates bone formation andbone loss, and orexin type 2 receptor agonist will be a therapeutic drugfor diseases related to bone loss such as osteoporosis, rheumatoidarthritis and the like (patent document 2).

In addition, it is suggested that orexin receptor agonist is useful forthe prophylaxis or treatment of sepsis, severe sepsis and septic shock,since the mortality was significantly improved by mere continuousadministration of orexin from the periphery in septic shock model mouse(patent document 3).

Therefore, a compound having an orexin type 2 receptor agonist activityis expected to be useful as a novel therapeutic drug for narcolepsy,idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, disturbanceof consciousness such as coma and the like, narcolepsy syndromeaccompanied by narcolepsy-like symptoms, hypersomnia syndromeaccompanied by daytime hypersomnia (e.g., Parkinson's disease,Guillain-Barre syndrome and Kleine Levin syndrome), Alzheimer, obesity,insulin resistance syndrome, cardiac failure, diseases related to boneloss, sepsis and the like, further, anesthetic antagonist, aprophylactic or therapeutic drug for side effects and complications dueto anesthesia.

Some of such compounds have been reported (patent document 4, patentdocument 5, patent document 6, non-patent document 13).

For example, such compounds include a compound represented by theformula

In addition, for example, such compounds include a compound representedby the formula

Also, for example, such compounds include a compound represented by theformula

However, it is considered that these compounds are not satisfactory interms of activity, pharmacokinetics or safety, and the development of acompound having an orexin type 2 receptor agonist activity is stilldesired.

DOCUMENT LIST Patent Documents

-   patent document 1: WO 2015/073707 A1-   patent document 2: WO 2015/048091 A1-   patent document 3: WO 2015/147240 A1-   patent document 4: U.S. Pat. No. 8,258,163 B2-   patent document 5: WO 2015/088000 A1-   patent document 6: WO 2014/198880 A1

Non-Patent Document

-   non-patent document 1: Cell, Vol. 92, 573-585, 1998-   non-patent document 2: Cell, Vol. 98, 365-376, 1999-   non-patent document 3: Proc. Natl. Acad. Sci. USA, Vol. 101,    4649-4654, 2004-   non-patent document 4: Cell, Vol. 98, 437-451, 1999-   non-patent document 5: Neuron, Vol. 38, 715-730, 2003-   non-patent document 6: CNS Drugs, Vol. 27, 83-90, 2013-   non-patent document 7: Cell Metabolism, Vol. 9, 64-76, 2009-   non-patent document 8: Neuroscience, Vol. 121, 855-863, 2003-   non-patent document 9: Respiration, Vol. 71, 575-579, 2004-   non-patent document 10: Peptides, Vol. 23, 1683-1688, 2002-   non-patent document 11: Journal of the American College of    Cardiology. Vol. 66, 2015, pages 2522-2533-   non-patent document 12: Brain, Vol. 130, 2007, pages 1586-1595-   non-patent document 13: Journal of Medicinal Chemistry. Vol. 58,    pages 7931-7937

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The present invention aims to provide a substituted piperidine compoundhaving an orexin type 2 receptor agonist activity.

Means of Solving the Problems

The present inventors have found that a compound represented by thefollowing formula (I) or a salt thereof (sometimes to be referred to ascompound (I) in the present specification) has an orexin type 2 receptoragonist activity. As a result of further studies, they have completedthe present invention.

Accordingly, the present invention relates to

[1] a compound represented by the formula:

wherein

R¹ is an acyl group, or a hydrogen atom;

R² is an optionally substituted 3- to 6-membered saturated cyclic group;and

R³ is an optionally substituted C₁₋₆ alkyl group, a mono- or di-C₁₋₆alkylamino group or a C₃₋₆ cycloalkyl group, or a salt thereof;

[2] the compound of [1], wherein R³ is an optionally substituted C₁₋₆alkyl group or a mono- or di-C₁₋₆ alkylamino group, or a salt thereof;

[3] the compound of [1] or [2], which is represented by the formula:

wherein R¹, R² and R³ are as defined in [1], or a salt thereof;[4] the compound of [1], [2] or [3], wherein R¹ is an acyl group, or asalt thereof;[5] the compound of [1], [2], [3] or [4], wherein R² is a C₃₋₆cycloalkyl group substituted by one optionally substituted phenyl group,or a salt thereof;[6] the compound of [1], [2], [3], [4] or [5], wherein R³ is anoptionally substituted C₁₋₆ alkyl group, or a salt thereof;[7] the compound of [1], [2] or [3], wherein R¹ is(1) a hydrogen atom,(2) an optionally substituted C₁₋₆ alkyl-carbonyl group,(3) an optionally substituted C₃₋₁₀ cycloalkyl-carbonyl group,(4) an optionally substituted C₁₋₆ alkoxy-carbonyl group,(5) an optionally substituted C₃₋₁₀ cycloalkyloxy-carbonyl group,(6) an optionally substituted C₆₋₁₄ aryl-carbonyl group,(7) an optionally substituted C₆₋₁₄ aryloxy-carbonyl group,(8) an optionally substituted 5- to 14-membered aromaticheterocyclylcarbonyl group,(9) an optionally substituted 3- to 14-membered non-aromaticheterocyclylcarbonyl group,(10) an optionally substituted mono- or di-C₁₋₆ alkyl-carbamoyl group,(11) an optionally substituted mono- or di-C₃₋₁₀ cycloalkyl-carbamoylgroup,(12) an optionally substituted mono- or di-C₆₋₁₄ aryl-carbamoyl group,(13) an optionally substituted C₁₋₆ alkylsulfonyl group,(14) an optionally substituted C₃₋₁₀ cycloalkylsulfonyl group,(15) an optionally substituted C₆₋₁₄ arylsulfonyl group,(16) an optionally substituted heterocyclyl-sulfonyl group,(17) an optionally substituted mono- or di-C₁₋₆ alkyl-sulfamoyl group or(18) an optionally substituted C₁₋₆ alkyl-carbonyl-carbonyl group;

R² is a C₃₋₆ cycloalkyl group or a 3- to 6-membered saturated monocyclicnon-aromatic heterocyclic group, each of which is optionally substitutedby 1 to 3 substituents selected from

(1) deuterium,

(2) a halogen atom,

(3) a hydroxy group,

(4) an optionally substituted C₁₋₆ alkyl group,

(5) a C₃₋₁₀ cycloalkyl group,

(6) an optionally substituted C₁₋₆ alkoxy group,

(7) an optionally substituted C₆₋₁₄ aryl group,

(8) a C₆₋₁₄ aryloxy group,

(9) a tri-C₁₋₆ alkylsilyloxy group,

(10) an optionally substituted 5- to 14-membered aromatic heterocyclicgroup and

(11) an optionally substituted C₆₋₁₄ aryl-carbonyl group; and

R³ is a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituentsselected from a halogen atom and a C₆₋₁₄ aryl group, or a mono- ordi-C₁₋₆ alkylamino group, or a salt thereof;

[8] the compound of [1], [2] or [3], wherein R¹ is

(1) a hydrogen atom,

(2) a C₁₋₆ alkyl-carbonyl group optionally substituted by 1 to 7substituents selected from

(i) a halogen atom, (ii) a cyano group, (iii) a hydroxy group, (iv) aC₃₋₁₀ cycloalkyl group, (v) a C₁₋₆ alkoxy group, (vi) a C₆₋₁₄ arylgroup, (vii) a C₆₋₁₄ aryloxy group, (viii) a pyrazolyl group, athiazolyl group, a pyrimidinyl group or a pyridazinyl group, each ofwhich is optionally substituted by an oxo group, (ix) a pyrazolyloxygroup optionally substituted by 1 to 3 C₁₋₆ alkyl groups, (x) a C₁₋₆alkyl-carbonyl group, (xi) a C₁₋₆ alkoxy-carbonyl group, (xii) a C₁₋₆alkyl-carbonyloxy group, (xiii) a C₁₋₆ alkylsulfonyl group, (xiv) amono- or di-C₁₋₆ alkylamino group, (xv) a C₁₋₆ alkyl-carbonylamino groupand (xvi) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl) amino group,(3) a C₃₋₁₀ cycloalkyl-carbonyl group optionally substituted by 1 to 3substituents selected from a halogen atom, a cyano group, a hydroxygroup, an oxo group and a C₁₋₆ alkyl group,(4) a C₁₋₆ alkoxy-carbonyl group optionally substituted by 1 to 6substituents selected from deuterium, a halogen atom and a C₆₋₁₄ arylgroup,(5) a C₃₋₁₀ cycloalkyloxy-carbonyl group optionally substituted by 1 to3 substituents selected from a C₁₋₆ alkyl group,(6) a C₆₋₁₄ aryl-carbonyl group optionally substituted by 1 to 3substituents selected from a halogen atom and a C₆₋₁₄ aryl group,(7) a C₆₋₁₄ aryloxy-carbonyl group,(8) a furylcarbonyl group, a thienylcarbonyl group, a pyrazolylcarbonylgroup, an isoxazolylcarbonyl group or a pyridylcarbonyl group, each ofwhich is optionally substituted by 1 to 3 substituents selected from aC₁₋₆ alkyl group,(9) an azetidinylcarbonyl group, an oxetanylcarbonyl group, apyrrolidinylcarbonyl group, a tetrahydrofuranylcarbonyl group, atetrahydropyranylcarbonyl group or a morpholinylcarbonyl group, each ofwhich is optionally substituted by 1 to 3 substituents selected from anoxo group, a C₁₋₆ alkyl-carbonyl group, a C₁₋₆ alkoxy-carbonyl group anda C₁₋₆ alkylsulfonyl group,(10) a mono- or di-C₁₋₆ alkyl-carbamoyl group optionally substituted by1 to 3 substituents selected from a halogen atom, a cyano group, ahydroxy group and a C₁₋₆ alkoxy group,(11) a mono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group,(12) a mono- or di-C₆₋₁₄ aryl-carbamoyl group,(13) a C₁₋₆ alkylsulfonyl group,(14) a C₃₋₁₀ cycloalkylsulfonyl group,(15) a C₆₋₁₄ arylsulfonyl group optionally substituted by 1 to 3 halogenatoms,(16) a thienylsulfonyl group, a pyrazolylsulfonyl group, animidazolylsulfonyl group, a pyridylsulfonyl group or adihydrochromenylsulfonyl group, each of which is optionally substitutedby 1 to 3 substituents selected from a C₁₋₆ alkyl group,(17) a mono- or di-C₁₋₆ alkyl-sulfamoyl group or(18) a C₁₋₆ alkyl-carbonyl-carbonyl group;

R² is a C₃₋₆ cycloalkyl group, a pyrrolidinyl group, a piperidinyl groupor a dioxanyl group, each of which is optionally substituted by 1 to 3substituents selected from

(1) deuterium,

(2) a halogen atom,

(3) a hydroxy group,

(4) a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituentsselected from a halogen atom and a C₆₋₁₄ aryl group,

(5) a C₃₋₁₀ cycloalkyl group,

(6) a C₁₋₆ alkoxy group optionally substituted by a C₃₋₁₀ cycloalkylgroup,

(7) a C₆₋₁₄ aryl group optionally substituted by 1 to 3 substituentsselected from a halogen atom, a cyano group, a C₁₋₆ alkyl groupoptionally substituted by 1 to 3 halogen atoms, a C₁₋₆ alkoxy groupoptionally substituted by 1 to 3 halogen atoms and a hydroxy group,(8) a C₆₋₁₄ aryloxy group,(9) a tri-C₁₋₆ alkylsilyloxy group,(10) a pyrazolyl group, a thiazolyl group, a pyridyl group, apyrimidinyl group, a quinazolinyl group, a benzothiazolyl group or anisoquinolinyl group, each of which is optionally substituted by 1 to 3substituents selected from a halogen atom, a C₁₋₆ alkyl group and a C₁₋₆alkoxy group, and(11) a C₆₋₁₄ aryl-carbonyl group; and

R³ is a C₁₋₆ alkyl group, or a mono- or di-C₁₋₆ alkylamino group, or asalt thereof;

[9] the compound of [1], [2] or [3], wherein R¹ is

(1) a hydrogen atom,

(2) a C₁₋₆ alkyl-carbonyl group optionally substituted by a hydroxygroup,

(3) a cyclopropanecarbonyl group,

(4) a C₁₋₆ alkoxy-carbonyl group or

(5) a mono- or di-C₁₋₆ alkyl-carbamoyl group;

R² is

(A) a cyclohexyl group optionally substituted by 1 to 3 substituentsselected from

(1) a C₁₋₆ alkyl group and

(2) a phenyl group optionally substituted by 1 to 3 substituentsselected from a halogen atom, a C₁₋₆ alkyl group optionally substitutedby 1 to 3 halogen atoms and a C₁₋₆ alkoxy group or

(B) a piperidinyl group optionally substituted by 1 to 3 pyrimidinylgroups; and

R³ is a C₁₋₆ alkyl group or a di-C₁₋₆ alkylamino group, or a saltthereof;

[10] the compound of [1], [2] or [3], wherein R¹ is

(1) a C₁₋₆ alkyl-carbonyl group optionally substituted by a hydroxygroup,

(2) a C₁₋₆ alkoxy-carbonyl group or

(3) a mono- or di-C₁₋₆ alkyl-carbamoyl group;

R² is a cyclohexyl group optionally substituted by 1 to 3 substituentsselected from

(1) a C₁₋₆ alkyl group and

(2) a phenyl group optionally substituted by 1 to 3 halogen atoms; and

R³ is a C₁₋₆ alkyl group, or a salt thereof;

[11] methyl(2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylateor a salt thereof;

[12]N-((2R,3S)-1-glycoloyl-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamideor a salt thereof;

[13](2R,3S)—N-ethyl-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)-3-((methylsulfonyl)amino)piperidine-1-carboxamideor a salt thereof;

[14] a medicament comprising the compound of [1]-[13] or a salt thereof;

[15] the medicament of [14], which is an orexin type 2 receptor agonist;

[16] the medicament of [14], which is a prophylactic or therapeuticagent for narcolepsy;

[17] the compound of [1]-[13] or a salt thereof for use in theprophylaxis or treatment of narcolepsy;

[18] a method of activating an orexin type 2 receptor in a mammal,comprising administering an effective amount of the compound of [1]-[13]or a salt thereof to the mammal;

[19] a method for the prophylaxis or treatment of narcolepsy in amammal, comprising administering an effective amount of the compound of[1]-[13] or a salt thereof to the mammal; and

[20] use of the compound of [1]-[13] or a salt thereof for themanufacture of a prophylactic or therapeutic agent for narcolepsy.

Effect of the Invention

The compound of the present invention has an orexin type 2 receptoragonist activity, and is useful as a prophylactic or therapeutic agentfor narcolepsy.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a powder X-ray diffraction chart of the crystals obtained inExample 5A.

DETAILED DESCRIPTION OF THE INVENTION

The definition of each substituent used in the present specification isdescribed in detail in the following. Unless otherwise specified, eachsubstituent has the following definition.

In the present specification, examples of the “halogen atom” includefluorine, chlorine, bromine and iodine.

In the present specification, examples of the “C₁₋₆ alkyl group” includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and2-ethylbutyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl group” include a C₁₋₆ alkyl group optionally having 1 to 7,preferably 1 to 5, a halogen atoms. Specific examples thereof includemethyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl,pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl,isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and6,6,6-trifluorohexyl.

In the present specification, examples of the “C₂₋₆ alkenyl group”include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and5-hexenyl.

In the present specification, examples of the “C₂₋₆ alkynyl group”include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkyl group”include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl and adamantyl.

In the present specification, examples of the “optionally halogenatedC₃₋₁₀ cycloalkyl group” include a C₃₋₁₀ cycloalkyl group optionallyhaving 1 to 7, preferably 1 to 5, a halogen atoms. Specific examplesthereof include cyclopropyl, 2,2-difluorocyclopropyl,2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkenyl group”include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl and cyclooctenyl.

In the present specification, examples of the “C₆₋₁₄ aryl group” includephenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

In the present specification, examples of the “C₇₋₁₆ aralkyl group”include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

In the present specification, examples of the “C₁₋₆ alkoxy group”include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkoxy group” include a C₁₋₆ alkoxy group optionally having 1 to 7,preferably 1 to 5, a halogen atoms. Specific examples thereof includemethoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “C₃₋₁₀ cycloalkyloxygroup” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

In the present specification, examples of the “C₁₋₆ alkylthio group”include methylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio, tert-butylthio, pentylthio and hexylthio.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylthio group” include a C₁₋₆ alkylthio group optionally having 1to 7, preferably 1 to 5, a halogen atoms. Specific examples thereofinclude methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,pentylthio and hexylthio.

In the present specification, examples of the “C₁₋₆ alkyl-carbonylgroup” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl,pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl,hexanoyl and heptanoyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl-carbonyl group” include a C₁₋₆ alkyl-carbonyl groupoptionally having 1 to 7, preferably 1 to 5, a halogen atoms. Specificexamples thereof include acetyl, chloroacetyl, trifluoroacetyl,trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

In the present specification, examples of the “C₁₋₆ alkoxy-carbonylgroup” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl andhexyloxycarbonyl.

In the present specification, examples of the “C₆₋₁₄ aryl-carbonylgroup” include benzoyl, 1-naphthoyl and 2-naphthoyl.

In the present specification, examples of the “C₇₋₁₆ aralkyl-carbonylgroup” include phenylacetyl and phenylpropionyl.

In the present specification, examples of the “5- to 14-memberedaromatic heterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl,thenoyl and furoyl.

In the present specification, examples of the “3- to 14-memberednon-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl,piperidinylcarbonyl and pyrrolidinylcarbonyl.

In the present specification, examples of the “mono- or di-C₁₋₆alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

In the present specification, examples of the “mono- or di-C₇₋₁₆aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.

In the present specification, examples of the “C₁₋₆ alkylsulfonyl group”include methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl andtert-butylsulfonyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylsulfonyl group” include a C₁₋₆ alkylsulfonyl group optionallyhaving 1 to 7, preferably 1 to 5, a halogen atoms. Specific examplesthereof include methylsulfonyl, difluoromethylsulfonyl,trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl,pentylsulfonyl and hexylsulfonyl.

In the present specification, examples of the “C₆₋₁₄ arylsulfonyl group”include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

In the present specification, examples of the “substituent” include ahalogen atom, a cyano group, a nitro group, an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, an acylgroup, an optionally substituted amino group, an optionally substitutedcarbamoyl group, an optionally substituted thiocarbamoyl group, anoptionally substituted sulfamoyl group, an optionally substitutedhydroxy group, an optionally substituted sulfanyl (SH) group and anoptionally substituted silyl group.

In the present specification, examples of the “hydrocarbon group”(including “hydrocarbon group” of “optionally substituted hydrocarbongroup”) include a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynylgroup, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group, a C₆₋₁₄aryl group and a C₇₋₁₆ aralkyl group.

In the present specification, examples of the “optionally substitutedhydrocarbon group” include a hydrocarbon group optionally havingsubstituent(s) selected from the following substituent group A.

[Substituent Group A]

(1) a halogen atom,

(2) a nitro group,

(3) a cyano group,

(4) an oxo group,

(5) a hydroxy group,

(6) an optionally halogenated C₁₋₆ alkoxy group,

(7) a C₆₋₁₄ aryloxy group (e.g., phenoxy, naphthoxy),

(8) a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy),

(9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,pyridyloxy),

(10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g.,morpholinyloxy, piperidinyloxy),

(11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy),

(12) a C₆₋₁₄ aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthoyloxy,2-naphthoyloxy),

(13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),

(14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,diethylcarbamoyloxy),

(15) a C₆₋₁₄ aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy,naphthylcarbamoyloxy),

(16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g.,nicotinoyloxy),

(17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group(e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),

(18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group (e.g.,methylsulfonyloxy, trifluoromethylsulfonyloxy),

(19) a C₆₋₁₄ arylsulfonyloxy group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy),

(20) an optionally halogenated C₁₋₆ alkylthio group,

(21) a 5- to 14-membered aromatic heterocyclic group,

(22) a 3- to 14-membered non-aromatic heterocyclic group,

(23) a formyl group,

(24) a carboxy group,

(25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,

(26) a C₆₋₁₄ aryl-carbonyl group,

(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,

(28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,

(29) a C₁₋₆ alkoxy-carbonyl group,

(30) a C₆₋₁₄ aryloxy-carbonyl group (e.g., phenyloxycarbonyl,1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),

(31) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl),

(32) a carbamoyl group,

(33) a thiocarbamoyl group,

(34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,

(35) a C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl),

(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl, thienylcarbamoyl),

(37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group (e.g.,morpholinylcarbamoyl, piperidinylcarbamoyl),

(38) an optionally halogenated C₁₋₆ alkylsulfonyl group,

(39) a C₆₋₁₄ arylsulfonyl group,

(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g.,pyridylsulfonyl, thienylsulfonyl),

(41) an optionally halogenated C₁₋₆ alkylsulfinyl group,

(42) a C₆₋₁₄ arylsulfinyl group (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl),

(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g.,pyridylsulfinyl, thienylsulfinyl),

(44) an amino group,

(45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino, ethylamino,propylamino, isopropylamino, butylamino, dimethylamino, diethylamino,dipropylamino, dibutylamino, N-ethyl-N-methylamino),

(46) a mono- or di-C₆₋₁₄ arylamino group (e.g., phenylamino),

(47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,pyridylamino),

(48) a C₇₋₁₆ aralkylamino group (e.g., benzylamino),

(49) a formylamino group,

(50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,propanoylamino, butanoylamino),

(51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl)amino group (e.g.,N-acetyl-N-methylamino),

(52) a C₆₋₁₄ aryl-carbonylamino group (e.g., phenylcarbonylamino,naphthylcarbonylamino),

(53) a C₁₋₆ alkoxy-carbonylamino group (e.g., methoxycarbonylamino,ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino,tert-butoxycarbonylamino),

(54) a C₇₋₁₆ aralkyloxy-carbonylamino group (e.g.,benzyloxycarbonylamino),

(55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,ethylsulfonylamino),

(56) a C₆₋₁₄ arylsulfonylamino group optionally substituted by a C₁₋₆alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino),

(57) an optionally halogenated C₁₋₆ alkyl group,

(58) a C₂₋₆ alkenyl group,

(59) a C₂₋₆ alkynyl group,

(60) a C₃₋₁₀ cycloalkyl group,

(61) a C₃₋₁₀ cycloalkenyl group and

(62) a C₆₋₁₄ aryl group.

The number of the above-mentioned substituents in the “optionallysubstituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to3. When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

In the present specification, examples of the “heterocyclic group”(including “heterocyclic group” of “optionally substituted heterocyclicgroup”) include (i) an aromatic heterocyclic group, (ii) a non-aromaticheterocyclic group and (iii) a 7- to 10-membered bridged heterocyclicgroup, each containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom.

In the present specification, examples of the “aromatic heterocyclicgroup” (including “5- to 14-membered aromatic heterocyclic group”)include a 5- to 14-membered (preferably 5- to 10-membered) aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “aromatic heterocyclic group” include 5- or6-membered monocyclic aromatic heterocyclic groups such as thienyl,furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and8- to 14-membered fused polycyclic (preferably bi or tricyclic) aromaticheterocyclic groups such as benzothiophenyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl,furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl,thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl,thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl,pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl,pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl,isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl and the like.

In the present specification, examples of the “non-aromatic heterocyclicgroup” (including “3- to 14-membered non-aromatic heterocyclic group”)include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “non-aromatic heterocyclic group” include 3-to 8-membered monocyclic non-aromatic heterocyclic groups such asaziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl,imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl,pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl,tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl,tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl,tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl,tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl,azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and thelike; and 9- to 14-membered fused polycyclic (preferably bi ortricyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl,dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl,dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl,tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl,isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl,tetrahydroquinoxalinyl, tetrahydrophenanthridinyl,hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl,tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl,tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacrydinyl,tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl andthe like.

In the present specification, preferable examples of the “7- to10-membered bridged heterocyclic group” include quinuclidinyl and7-azabicyclo[2.2.1]heptanyl.

In the present specification, examples of the “nitrogen-containingheterocyclic group” include the “heterocyclic group” containing at leastone nitrogen atom as a ring-constituting atom.

In the present specification, examples of the “optionally substitutedheterocyclic group” include a heterocyclic group optionally havingsubstituent(s) selected from the aforementioned substituent group A.

The number of the substituents in the “optionally substitutedheterocyclic group” is, for example, 1 to 3. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

In the present specification, examples of the “acyl group” include aformyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group,a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group,each optionally having “1 or 2 substituents selected from a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀cycloalkenyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a 5- to14-membered aromatic heterocyclic group and a 3- to 14-memberednon-aromatic heterocyclic group, each of which optionally has 1 to 3substituents selected from a halogen atom, an optionally halogenatedC₁₋₆ alkoxy group, a hydroxy group, a nitro group, a cyano group, anamino group and a carbamoyl group”.

Examples of the “acyl group” also include a hydrocarbon-sulfonyl group,a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group and aheterocyclylsulfinyl group.

Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bondedsulfonyl group, the heterocyclylsulfonyl group means a heterocyclicgroup-bonded sulfonyl group, the hydrocarbon-sulfinyl group means ahydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinylgroup means a heterocyclic group-bonded sulfinyl group.

Preferable examples of the “acyl group” include a formyl group, acarboxy group, a C₁₋₆ alkyl-carbonyl group, a C₂₋₆ alkenyl-carbonylgroup (e.g., crotonoyl), a C₃₋₁₀ cycloalkyl-carbonyl group (e.g.,cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,cycloheptanecarbonyl), a C₃₋₁₀ cycloalkenyl-carbonyl group (e.g.,2-cyclohexenecarbonyl), a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a C₆₋₁₄aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), aC₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl), a carbamoyl group, a mono- or di-C₁₋₆alkyl-carbamoyl group, a mono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g.,diallylcarbamoyl), a mono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbamoyl group (e.g.,phenylcarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-carbamoyl group, a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl), a thiocarbamoyl group, a mono- or di-C₁₋₆alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to14-membered aromatic heterocyclylthiocarbamoyl group (e.g.,pyridylthiocarbamoyl), a sulfino group, a C₁₋₆ alkylsulfinyl group(e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a C₁₋₆alkylsulfonyl group, a C₆₋₁₄ arylsulfonyl group, a phosphono group and amono- or di-C₁₋₆ alkylphosphono group (e.g., dimethylphosphono,diethylphosphono, diisopropylphosphono, dibutylphosphono).

In the present specification, examples of the “optionally substitutedamino group” include an amino group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from substituentgroup A”.

Preferable examples of the optionally substituted amino group include anamino group, a mono- or di-(optionally halogenated C₁₋₆ alkyl)aminogroup (e.g., methylamino, trifluoromethylamino, dimethylamino,ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C₂₋₆alkenylamino group (e.g., diallylamino), a mono- or di-C₃₋₁₀cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono-or di-C₆₋₁₄ arylamino group (e.g., phenylamino), a mono- or di-C₇₋₁₆aralkylamino group (e.g., benzylamino, dibenzylamino), a mono- ordi-(optionally halogenated C₁₋₆ alkyl)-carbonylamino group (e.g.,acetylamino, propionylamino), a mono- or di-C₆₋₁₄ aryl-carbonylaminogroup (e.g., benzoylamino), a mono- or di-C₇₋₁₆ aralkyl-carbonylaminogroup (e.g., benzylcarbonylamino), a mono- or di-5- to 14-memberedaromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino,isonicotinoylamino), a mono- or di-3- to 14-membered non-aromaticheterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), amono- or di-C₁₋₆ alkoxy-carbonylamino group (e.g.,tert-butoxycarbonylamino), a 5- to 14-membered aromaticheterocyclylamino group (e.g., pyridylamino), a carbamoylamino group, a(mono- or di-C₁₋₆ alkyl-carbamoyl)amino group (e.g.,methylcarbamoylamino), a (mono- or di-C₇₋₁₆ aralkyl-carbamoyflaminogroup (e.g., benzylcarbamoylamino), a C₁₋₆ alkylsulfonylamino group(e.g., methylsulfonylamino, ethylsulfonylamino), a C₆₋₁₄arylsulfonylamino group (e.g., phenylsulfonylamino), a (C₁₋₆ alkyl)(C₁₋₆ alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino) and a(C₁₋₆ alkyl) (C₆₋₁₄ aryl-carbonyl)amino group (e.g.,N-benzoyl-N-methylamino).

In the present specification, examples of the “optionally substitutedcarbamoyl group” include a carbamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted carbamoyl groupinclude a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group, amono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g., diallylcarbamoyl), amono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C₇₋₁₆aralkyl-carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbonyl-carbamoylgroup (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl).

In the present specification, examples of the “optionally substitutedthiocarbamoyl group” include a thiocarbamoyl group optionally having “1or 2 substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkylgroup, a C₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted thiocarbamoyl groupinclude a thiocarbamoyl group, a mono- or di-C₁₋₆ alkyl-thiocarbamoylgroup (e.g., methylthiocarbamoyl, ethylthiocarbamoyl,dimethylthiocarbamoyl, diethylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- ordi-C₁₋₆ alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl,propionylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-thiocarbamoylgroup (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromaticheterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl).

In the present specification, examples of the “optionally substitutedsulfamoyl group” include a sulfamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group and a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted sulfamoyl groupinclude a sulfamoyl group, a mono- or di-C₁₋₆ alkyl-sulfamoyl group(e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl,diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C₂₋₆alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C₃₋₁₀cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl,cyclohexylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-sulfamoyl group (e.g.,phenylsulfamoyl), a mono- or di-C₇₋₁₆ aralkyl-sulfamoyl group (e.g.,benzylsulfamoyl, phenethylsulfamoyl), a mono- or di-C₁₋₆alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl,propionylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-sulfamoyl group(e.g., benzoylsulfamoyl) and a 5- to 14-membered aromaticheterocyclylsulfamoyl group (e.g., pyridylsulfamoyl).

In the present specification, examples of the “optionally substitutedhydroxy group” include a hydroxyl group optionally having “a substituentselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a C₁₋₆alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from substituentgroup A”.

Preferable examples of the optionally substituted hydroxy group includea hydroxy group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxy group (e.g.,allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C₃₋₁₀cycloalkyloxy group (e.g., cyclohexyloxy), a C₆₋₁₄ aryloxy group (e.g.,phenoxy, naphthyloxy), a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy,phenethyloxy), a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy,propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C₆₋₁₄aryl-carbonyloxy group (e.g., benzoyloxy), a C₇₋₁₆ aralkyl-carbonyloxygroup (e.g., benzylcarbonyloxy), a 5- to 14-membered aromaticheterocyclylcarbonyloxy group (e.g., nicotinoyloxy), a 3- to 14-memberednon-aromatic heterocyclylcarbonyloxy group (e.g.,piperidinylcarbonyloxy), a C₁₋₆ alkoxy-carbonyloxy group (e.g.,tert-butoxycarbonyloxy), a 5- to 14-membered aromatic heterocyclyloxygroup (e.g., pyridyloxy), a carbamoyloxy group, a C₁₋₆alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), a C₇₋₁₆aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), a C₁₋₆alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and aC₆₋₁₄ arylsulfonyloxy group (e.g., phenylsulfonyloxy).

In the present specification, examples of the “optionally substitutedsulfanyl group” include a sulfanyl group optionally having “asubstituent selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group and a 5- to14-membered aromatic heterocyclic group, each of which optionally has 1to 3 substituents selected from substituent group A” and a halogenatedsulfanyl group.

Preferable examples of the optionally substituted sulfanyl group includea sulfanyl (—SH) group, a C₁₋₆ alkylthio group, a C₂₋₆ alkenylthio group(e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C₃₋₁₀cycloalkylthio group (e.g., cyclohexylthio), a C₆₋₁₄ arylthio group(e.g., phenylthio, naphthylthio), a C₇₋₁₆ aralkylthio group (e.g.,benzylthio, phenethylthio), a C₁₋₆ alkyl-carbonylthio group (e.g.,acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), aC₆₋₁₄ aryl-carbonylthio group (e.g., benzoylthio), a 5- to 14-memberedaromatic heterocyclylthio group (e.g., pyridylthio) and a halogenatedthio group (e.g., pentafluorothio).

In the present specification, examples of the “optionally substitutedsilyl group” include a silyl group optionally having “1 to 3substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group and a C₇₋₁₆ aralkyl group,each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted silyl group include atri-C₁₋₆ alkylsilyl group (e.g., trimethylsilyl,tert-butyl(dimethyl)silyl).

In the present specification, examples of the “C₃₋₆ cycloalkyl group”include the above-mentioned “C₃₋₁₀ cycloalkyl group” wherein the carbonnumber is 3 to 6.

In the present specification, examples of the “3- to 6-memberedsaturated cyclic group” include the above-mentioned “C₃₋₁₀ cycloalkylgroup” wherein the carbon number is 3 to 6 (C₃₋₆ cycloalkyl group), theabove-mentioned “3- to 8-membered monocyclic non-aromatic heterocyclicgroup” which is 3- to 6-membered and saturated (3- to 6-memberedsaturated monocyclic non-aromatic heterocyclic group).

In the present specification, examples of the “mono- or di-C₁₋₆alkylamino group” include an amino group mono- or di-substituted by theabove-mentioned “C₁₋₆ alkyl group”. When it is a di-C₁₋₆ alkylaminogroup, two C₁₋₆ alkyl groups may be the same or different (e.g.,N-ethyl-N-methylamino etc.).

The definition of each symbol in the formula (I) is described in detailbelow.

R¹ is an acyl group, or a hydrogen atom.

As the “acyl group” for R¹, the above-mentioned “acyl group” can bementioned.

R¹ is preferably (1) a hydrogen atom, (2) an optionally substituted C₁₋₆alkyl-carbonyl group (e.g., methylcarbonyl, ethylcarbonyl,propylcarbonyl, isopropylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl,neopentylcarbonyl), (3) an optionally substituted C₃₋₁₀ (preferablyC₃₋₆) cycloalkyl-carbonyl group (e.g., cyclopropanecarbonyl,cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl), (4) anoptionally substituted C₁₋₆ alkoxy-carbonyl group (e.g.,methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,tert-butoxycarbonyl), (5) an optionally substituted C₃₋₁₀cycloalkyloxy-carbonyl group (e.g., cyclopropyloxycarbonyl), (6) anoptionally substituted C₆₋₁₄ aryl-carbonyl group (e.g., phenylcarbonyl),(7) an optionally substituted C₆₋₁₄ aryloxy-carbonyl group (e.g.,phenyloxycarbonyl), (8) an optionally substituted 5- to 14-memberedaromatic heterocyclylcarbonyl group (e.g., furylcarbonyl,thienylcarbonyl, pyrazolylcarbonyl, isoxazolylcarbonyl,pyridylcarbonyl), (9) an optionally substituted 3- to 14-memberednon-aromatic heterocyclylcarbonyl group (e.g., azetidinylcarbonyl,oxetanylcarbonyl, pyrrolidinylcarbonyl, tetrahydrofuranylcarbonyl,tetrahydropyranylcarbonyl, morpholinylcarbonyl), (10) an optionallysubstituted mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl,dimethylcarbamoyl), (11) an optionally substituted mono- or di-C₃₋₁₀cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl), (12) anoptionally substituted mono- or di-C₆₋₁₄ aryl-carbamoyl group (e.g.,phenylcarbamoyl), (13) an optionally substituted C₁₋₆ alkylsulfonylgroup (e.g., methylsulfonyl), (14) an optionally substituted C₃₋₁₀cycloalkylsulfonyl group (e.g., cyclopropylsulfonyl), (15) an optionallysubstituted C₆₋₁₄ arylsulfonyl group (e.g., phenylsulfonyl), (16) anoptionally substituted heterocyclyl-sulfonyl group (e.g.,thienylsulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, pyridylsulfonyl,dihydrochromenylsulfonyl), (17) an optionally substituted mono- ordi-C₁₋₆ alkyl-sulfamoyl group (e.g., dimethylsulfamoyl) and (18) anoptionally substituted C₁₋₆ alkyl-carbonyl-carbonyl group (e.g.,methylcarbonylcarbonyl).

R¹ is more preferably (1) a hydrogen atom, (2) a C₁₋₆ alkyl-carbonylgroup (e.g., methylcarbonyl, ethylcarbonyl, propylcarbonyl,isopropylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl,neopentylcarbonyl) optionally substituted by 1 to 7 substituentsselected from a halogen atom (e.g., fluorine atom), a cyano group, ahydroxy group, a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), a C₁₋₆alkoxy group (e.g., methoxy), a C₆₋₁₄ aryl group (e.g., phenyl), a C₆₋₁₄aryloxy group (e.g., phenoxy), a 5- to 14-membered aromatic heterocyclicgroup (e.g., pyrazolyl, thiazolyl, pyrimidinyl, pyridazinyl) optionallysubstituted by an oxo group, a 5- to 14-membered aromaticheterocyclyloxy group (e.g., pyrazolyloxy) optionally substituted by 1to 3 substituents selected from a C₁₋₆ alkyl group (e.g., methyl), aC₁₋₆ alkyl-carbonyl group (e.g., methylcarbonyl), a C₁₋₆ alkoxy-carbonylgroup (e.g., methoxycarbonyl), a C₁₋₆ alkyl-carbonyloxy group (e.g.,methylcarbonyloxy), a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl), amono- or di-C₁₋₆ alkylamino group (e.g., dimethylamino), a C₁₋₆alkyl-carbonylamino group (e.g., acetylamino) and a (C₁₋₆ alkyl) (C₁₋₆alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino), (3) a C₃₋₁₀(preferably C₃₋₆) cycloalkyl-carbonyl group (e.g., cyclopropanecarbonyl,cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl)optionally substituted by 1 to 3 substituents selected from a halogenatom (e.g., fluorine atom), a cyano group, a hydroxy group, an oxo groupand a C₁₋₆ alkyl group (e.g., methyl), (4) a C₁₋₆ alkoxy-carbonyl group(e.g., methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,tert-butoxycarbonyl) optionally substituted by 1 to 6 substituentsselected from deuterium, a halogen atom (e.g., fluorine atom) and aC₆₋₁₄ aryl group (e.g., phenyl), (5) a C₃₋₁₀ cycloalkyloxy-carbonylgroup (e.g., cyclopropyloxycarbonyl) optionally substituted by 1 to 3substituents selected from a C₁₋₆ alkyl group (e.g., methyl), (6) aC₆₋₁₄ aryl-carbonyl group (e.g., phenylcarbonyl) optionally substitutedby 1 to 3 substituents selected from a halogen atom (e.g., fluorineatom, chlorine atom) and a C₆₋₁₄ aryl group (e.g., phenyl), (7) a C₆₋₁₄aryloxy-carbonyl group (e.g., phenyloxycarbonyl), (8) a 5- to14-membered aromatic heterocyclylcarbonyl group (e.g., furylcarbonyl,thienylcarbonyl, pyrazolylcarbonyl, isoxazolylcarbonyl, pyridylcarbonyl)optionally substituted by 1 to 3 substituents selected from a C₁₋₆ alkylgroup (e.g., methyl), (9) a 3- to 14-membered non-aromaticheterocyclylcarbonyl group (e.g., azetidinylcarbonyl, oxetanylcarbonyl,pyrrolidinylcarbonyl, tetrahydrofuranylcarbonyl,tetrahydropyranylcarbonyl, morpholinylcarbonyl) optionally substitutedby 1 to 3 substituents selected from an oxo group, a C₁₋₆ alkyl-carbonylgroup (e.g., methylcarbonyl), a C₁₋₆ alkoxy-carbonyl group (e.g.,tert-butoxycarbonyl) and a C₁₋₆ alkylsulfonyl group (e.g.,methylsulfonyl), (10) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl,dimethylcarbamoyl) optionally substituted by 1 to 3 substituentsselected from a halogen atom (e.g., fluorine atom), a cyano group, ahydroxy group and a C₁₋₆ alkoxy group (e.g., methoxy), (11) a mono- ordi-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl), (12) amono- or di-C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl), (13) aC₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl), (14) a C₃₋₁₀cycloalkylsulfonyl group (e.g., cyclopropylsulfonyl), (15) a C₆₋₁₄arylsulfonyl group (e.g., phenylsulfonyl) optionally substituted by 1 to3 halogen atoms (e.g., chlorine atom), (16) a heterocyclyl-sulfonylgroup (e.g., thienylsulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl,pyridylsulfonyl, dihydrochromenylsulfonyl) optionally substituted by 1to 3 substituents selected from a C₁₋₆ alkyl group (e.g., methyl), (17)a mono- or di-C₁₋₆ alkyl-sulfamoyl group (e.g., dimethylsulfamoyl) or(18) a C₁₋₆ alkyl-carbonyl-carbonyl group (e.g.,methylcarbonylcarbonyl).

In another embodiment of the present invention, R¹ is preferably an acylgroup.

In a still another embodiment of the present invention, R¹ is preferablya C₁₋₆ alkyl-carbonyl group optionally substituted by one hydroxy group,a C₁₋₆ alkoxy-carbonyl group, a C₃₋₆ cycloalkyl-carbonyl group or amono- or di-C₁₋₆ alkyl-carbamoyl group.

In yet another embodiment of the present invention, R¹ is preferably ahydrogen atom.

In another embodiment of the present invention, R¹ is preferably (1) ahydrogen atom, (2) a C₁₋₆ alkyl-carbonyl group optionally substituted bya hydroxy group, (3) a cyclopropanecarbonyl group, (4) a C₁₋₆alkoxy-carbonyl group or (5) a mono- or di-C₁₋₆ alkyl-carbamoyl group.

In another embodiment of the present invention, R¹ is preferably (1) aC₁₋₆ alkyl-carbonyl group optionally substituted by a hydroxy group, (2)a C₁₋₆ alkoxy-carbonyl group or (3) a mono- or di-C₁₋₆ alkyl-carbamoylgroup.

In another embodiment of the present invention, R¹ is preferably a C₁₋₆alkoxy-carbonyl group (preferably methoxycarbonyl).

In another embodiment of the present invention, R¹ is preferably a C₁₋₆alkyl-carbonyl group optionally substituted by a hydroxy group.

In another embodiment of the present invention, R¹ is preferably a mono-or di-C₁₋₆ alkyl-carbamoyl group.

R² is an optionally substituted 3- to 6-membered saturated cyclic group.

As the “3- to 6-membered saturated cyclic group” of the “optionallysubstituted 3- to 6-membered saturated cyclic group” for R², a C₃₋₆cycloalkyl group (e.g., cyclobutyl, cyclopentyl, cyclohexyl) or a 3- to6-membered saturated monocyclic non-aromatic heterocyclic group (e.g.,pyrrolidinyl, piperidinyl, dioxanyl) can be mentioned.

As the substituent of the “optionally substituted 3- to 6-memberedsaturated cyclic group” for R², the above-mentioned “substituent” can bementioned, and (1) deuterium, (2) a halogen atom (e.g., fluorine atom),(3) a hydroxy group, (4) an optionally substituted C₁₋₆ alkyl group(e.g., methyl, isopropyl), (5) a C₃₋₁₀ cycloalkyl group (e.g.,cyclohexyl), (6) an optionally substituted C₁₋₆ alkoxy group (e.g.,methoxy), (7) an optionally substituted C₆₋₁₄ aryl group (e.g., phenyl),(8) a C₆₋₁₄ aryloxy group (e.g., phenoxy), (9) a tri-C₁₋₆ alkylsilyloxygroup (e.g., tert-butyl(dimethyl)silyloxy), (10) an optionallysubstituted 5- to 14-membered aromatic heterocyclic group (e.g.,pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl,benzothiazolyl, isoquinolinyl) or (11) an optionally substituted C₆₋₁₄aryl-carbonyl group (e.g., benzoyl) is preferable, (1) deuterium, (2) ahalogen atom (e.g., fluorine atom), (3) a hydroxy group, (4) a C₁₋₆alkyl group (e.g., methyl, isopropyl) optionally substituted by 1 to 3substituents selected from a halogen atom (e.g., fluorine atom) and aC₆₋₁₄ aryl group (e.g., phenyl), (5) a C₃₋₁₀ cycloalkyl group (e.g.,cyclohexyl), (6) a C₁₋₆ alkoxy group (e.g., methoxy) optionallysubstituted by a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), (7) a C₆₋₁₄aryl group (e.g., phenyl) optionally substituted by 1 to 3 substituentsselected from a halogen atom (e.g., fluorine atom, chlorine atom), acyano group, a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionallysubstituted by 1 to 3 halogen atoms (e.g., fluorine atom), a C₁₋₆ alkoxygroup (e.g., methoxy) optionally substituted by 1 to 3 halogen atoms(e.g., fluorine atom) and a hydroxy group, (8) a C₆₋₁₄ aryloxy group(e.g., phenoxy), (9) a tri-C₁₋₆ alkylsilyloxy group (e.g.,tert-butyl(dimethyl)silyloxy), (10) a 5- to 14-membered aromaticheterocyclic group (e.g., pyrazolyl, thiazolyl, pyridyl, pyrimidinyl,quinazolinyl, benzothiazolyl, isoquinolinyl) optionally substituted by 1to 3 substituents selected from a halogen atom (e.g., fluorine atom,chlorine atom), a C₁₋₆ alkyl group (e.g., methyl) and a C₁₋₆ alkoxygroup (e.g., methoxy) or (11) a C₆₋₁₄ aryl-carbonyl group (e.g.,benzoyl) is more preferable.

In the present specification, when the “optionally substituted 3- to6-membered saturated cyclic group” for R² has two substituents on onecarbon constituting the “3- to 6-membered saturated cyclic group”, itincludes an embodiment wherein said two substituents are bonded to eachother to form a spiro ring system (e.g.,3H-spiro[2-benzofuran-1,1′-cyclohexane]-4′-yl,1,4-dioxaspiro[4.5]dec-8-yl) together with the “3- to 6-memberedsaturated cyclic group”.

R² is preferably a C₃₋₆ cycloalkyl group (e.g., cyclobutyl, cyclopentyl,cyclohexyl) or a 3- to 6-membered saturated monocyclic non-aromaticheterocyclic group (e.g., pyrrolidinyl, piperidinyl, dioxanyl), each ofwhich is optionally substituted by 1 to 3 substituents selected from (1)deuterium, (2) a halogen atom (e.g., fluorine atom), (3) a hydroxygroup, (4) an optionally substituted C₁₋₆ alkyl group (e.g., methyl,isopropyl), (5) a C₃₋₁₀ cycloalkyl group (e.g., cyclohexyl), (6) anoptionally substituted C₁₋₆ alkoxy group (e.g., methoxy), (7) anoptionally substituted C₆₋₁₄ aryl group (e.g., phenyl), (8) a C₆₋₁₄aryloxy group (e.g., phenoxy), (9) a tri-C₁₋₆ alkylsilyloxy group (e.g.,tert-butyl(dimethyl)silyloxy), (10) an optionally substituted 5- to14-membered aromatic heterocyclic group (e.g., pyrazolyl, thiazolyl,pyridyl, pyrimidinyl, quinazolinyl, benzothiazolyl, isoquinolinyl) and(11) an optionally substituted C₆₋₁₄ aryl-carbonyl group (e.g.,benzoyl), more preferably a C₃₋₆ cycloalkyl group (e.g., cyclobutyl,cyclopentyl, cyclohexyl) or a 3- to 6-membered saturated monocyclicnon-aromatic heterocyclic group (e.g., pyrrolidinyl, piperidinyl,dioxanyl), each of which is optionally substituted by 1 to 3substituents selected from (1) deuterium, (2) a halogen atom (e.g.,fluorine atom), (3) a hydroxy group, (4) a C₁₋₆ alkyl group (e.g.,methyl, isopropyl) optionally substituted by 1 to 3 substituentsselected from a halogen atom (e.g., fluorine atom) and a C₆₋₁₄ arylgroup (e.g., phenyl), (5) a C₃₋₁₀ cycloalkyl group (e.g., cyclohexyl),(6) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted by aC₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), (7) a C₆₋₁₄ aryl group(e.g., phenyl) optionally substituted by 1 to 3 substituents selectedfrom a halogen atom (e.g., fluorine atom, chlorine atom), a cyano group,a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1 to3 halogen atoms (e.g., fluorine atom), a C₁₋₆ alkoxy group (e.g.,methoxy) optionally substituted 1 to 3 halogen atoms (e.g., fluorineatom) and a hydroxy group, (8) a C₆₋₁₄ aryloxy group (e.g., phenoxy),(9) a tri-C₁₋₆ alkylsilyloxy group (e.g., tert-butyl(dimethyl)silyloxy),(10) a 5- to 14-membered aromatic heterocyclic group (e.g., pyrazolyl,thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, benzothiazolyl,isoquinolinyl) optionally substituted by 1 to 3 substituents selectedfrom a halogen atom (e.g., fluorine atom, chlorine atom), a C₁₋₆ alkylgroup (e.g., methyl) and a C₁₋₆ alkoxy group (e.g., methoxy) and (11) aC₆₋₁₄ aryl-carbonyl group (e.g., benzoyl).

R² is further more preferably, (A) a C₃₋₆ cycloalkyl group (e.g.,cyclobutyl, cyclopentyl, cyclohexyl) optionally substituted by 1 to 3substituents selected from (1) deuterium, (2) a halogen atom (e.g.,fluorine atom), (3) a hydroxy group, (4) a C₁₋₆ alkyl group (e.g.,methyl, isopropyl) optionally substituted by 1 to 3 substituentsselected from a halogen atom (e.g., fluorine atom) and a C₆₋₁₄ arylgroup (e.g., phenyl), (5) a C₃₋₁₀ cycloalkyl group (e.g., cyclohexyl),(6) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted by aC₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), (7) a C₆₋₁₄ aryl group(e.g., phenyl) optionally substituted by 1 to 3 substituents selectedfrom a halogen atom (e.g., fluorine atom, chlorine atom), a cyano group,a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted by 1 to3 halogen atoms (e.g., fluorine atom), a C₁₋₆ alkoxy group (e.g.,methoxy) optionally substituted by 1 to 3 halogen atoms (e.g., fluorineatom) and a hydroxy group, (8) a C₆₋₁₄ aryloxy group (e.g., phenoxy),(9) a tri-C₁₋₆ alkylsilyloxy group (e.g., tert-butyl(dimethyl)silyloxy),(10) a 5- to 14-membered aromatic heterocyclic group (e.g., pyrazolyl,thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, benzothiazolyl,isoquinolinyl) optionally substituted by 1 to 3 substituents selectedfrom a halogen atom, a C₁₋₆ alkyl group (e.g., methyl) and a C₁₋₆ alkoxygroup (e.g., methoxy) and (11) a C₆₋₁₄ aryl-carbonyl group (e.g.,benzoyl) or (B) a 3- to 6-membered saturated monocyclic non-aromaticheterocyclic group (e.g., pyrrolidinyl, piperidinyl, dioxanyl)optionally substituted by 1 to 3 substituents selected from (1) ahalogen atom (e.g., fluorine atom), (2) a C₁₋₆ alkyl group (e.g.,methyl), (3) a C₆₋₁₄ aryl group (e.g., phenyl) optionally substituted by1 to 3 substituents selected from a halogen atom (e.g., fluorine atom,chlorine atom), a C₁₋₆ alkyl group (e.g., methyl) optionally substitutedby 1 to 3 halogen atoms (e.g., fluorine atom) and a C₁₋₆ alkoxy group(e.g., methoxy) and (4) a 5- to 14-membered aromatic heterocyclic group(e.g., thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, benzothiazolyl,isoquinolinyl) optionally substituted by 1 to 3 substituents selectedfrom a halogen atom (e.g., fluorine atom, chlorine atom), a C₁₋₆ alkylgroup (e.g., methyl) and a C₁₋₆ alkoxy group (e.g., methoxy).

In another embodiment of the present invention, R² is preferably a C₃₋₆cycloalkyl group substituted by one optionally substituted phenyl group.

In a still another embodiment of the present invention, R² is preferablya C₃₋₆ cycloalkyl group substituted by one phenyl group optionallysubstituted by 1 to 3 substituents selected from a halogen atom, a C₁₋₆alkyl group optionally substituted by 1 to 3 halogen atoms, and a C₁₋₆alkoxy group.

In a yet another embodiment of the present invention, R² is preferably apiperidinyl group substituted by one pyrimidinyl group.

In another embodiment of the present invention, R² is preferably a C₃₋₆cycloalkyl group, a pyrrolidinyl group, a piperidinyl group or adioxanyl group, each of which is optionally substituted by 1 to 3substituents selected from (1) deuterium, (2) a halogen atom, (3) ahydroxy group, (4) a C₁₋₆ alkyl group optionally substituted by 1 to 3substituents selected from a halogen atom and a C₆₋₁₄ aryl group, (5) aC₃₋₁₀ cycloalkyl group, (6) a C₁₋₆ alkoxy group optionally substitutedby a C₃₋₁₀ cycloalkyl group, (7) a C₆₋₁₄ aryl group optionallysubstituted by 1 to 3 substituents selected from a halogen atom, a cyanogroup, a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogenatoms, a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogenatoms and a hydroxy group, (8) a C₆₋₁₄ aryloxy group, (9) a tri-C₁₋₆alkylsilyloxy group, (10) a pyrazolyl group, a thiazolyl group, apyridyl group, a pyrimidinyl group, quinazolinyl group, a benzothiazolylgroup or an isoquinolinyl group, each of which is optionally substitutedby 1 to 3 substituents selected from a halogen atom, a C₁₋₆ alkyl groupand a C₁₋₆ alkoxy group, and (11) a C₆₋₁₄ aryl-carbonyl group.

In another embodiment of the present invention, R² is preferably acyclobutyl group, a cyclopentyl group, a cyclohexyl group, apyrrolidinyl group, a piperidinyl group or a dioxanyl group, each ofwhich is optionally substituted by 1 to 3 substituents selected from (1)deuterium, (2) a halogen atom, (3) a hydroxy group, (4) a C₁₋₆ alkylgroup optionally substituted by 1 to 3 substituents selected from ahalogen atom and a phenyl group, (5) a cyclohexyl group, (6) a C₁₋₆alkoxy group optionally substituted by a cyclopropyl group, (7) a phenylgroup optionally substituted by 1 to 3 substituents selected from ahalogen atom, a cyano group, a C₁₋₆ alkyl group optionally substitutedby 1 to 3 halogen atoms, a C₁₋₆ alkoxy group optionally substituted by 1to 3 halogen atoms and a hydroxy group, (8) a phenoxy group, (9) atri-C₁₋₆ alkylsilyloxy group, (10) a pyrazolyl group, a thiazolyl group,a pyridyl group, a pyrimidinyl group, a quinazolinyl group, abenzothiazolyl group or an isoquinolinyl group, each of which isoptionally substituted by 1 to 3 substituents selected from a halogenatom, a C₁₋₆ alkyl group and a C₁₋₆ alkoxy group, and (11) a benzoylgroup.

In another embodiment of the present invention, R² is preferably (A) acyclohexyl group optionally substituted by 1 to 3 substituents selectedfrom (1) a C₁₋₆ alkyl group and (2) a phenyl group optionallysubstituted by 1 to 3 substituents selected from a halogen atom, a C₁₋₆alkyl group optionally substituted by 1 to 3 halogen atoms and a C₁₋₆alkoxy group or (B) a piperidinyl group optionally substituted by 1 to 3pyrimidinyl groups.

In another embodiment of the present invention, R² is preferably acyclohexyl group optionally substituted by 1 to 3 substituents selectedfrom (1) a C₁₋₆ alkyl group and (2) a phenyl group optionallysubstituted by 1 to 3 halogen atoms.

In another embodiment of the present invention, R² is preferably acyclohexyl group optionally substituted by a phenyl group.

In another embodiment of the present invention, R² is preferably acyclohexyl group optionally substituted by a phenyl group optionallysubstituted by 1 to 3 halogen atoms.

In another embodiment of the present invention, R² is preferably acyclohexyl group optionally substituted by a C₁₋₆ alkyl group.

R³ is an optionally substituted C₁₋₆ alkyl group, a mono- or di-C₁₋₆alkylamino group or a C₃₋₆ cycloalkyl group; preferably an optionallysubstituted C₁₋₆ alkyl group, or a mono- or di-C₁₋₆ alkylamino group.

As the substituent of the “optionally substituted C₁₋₆ alkyl group” forR³, the above-mentioned “substituent” can be mentioned, and a halogenatom (e.g., fluorine atom) or a C₆₋₁₄ aryl group (e.g., phenyl) ispreferable.

R³ is preferably a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl,isopropyl, isobutyl) optionally substituted by 1 to 3 substituentsselected from a halogen atom (e.g., fluorine atom) and a C₆₋₁₄ arylgroup (e.g., phenyl), or a mono- or di-C₁₋₆ alkylamino group (e.g.,ethylamino, dimethylamino), more preferably, a C₁₋₆ alkyl group (e.g.,methyl), or a mono- or di-C₁₋₆ alkylamino group (e.g., dimethylamino).

In another embodiment of the present invention, R³ is preferably anoptionally substituted C₁₋₆ alkyl group.

In another embodiment of the present invention, R³ is preferably a C₁₋₆alkyl group or a di-C₁₋₆ alkylamino group, more preferably a C₁₋₆ alkylgroup (preferably methyl).

In a preferable embodiment of the present invention, compound (I) isrepresented by the formula:

wherein R¹, R² and R³ are as defined above.

As a preferable embodiment of compound (I), the following compounds canbe mentioned.

[Compound I-1]

Compound (I) wherein R¹ is (1) a hydrogen atom, (2) an optionallysubstituted C₁₋₆ alkyl-carbonyl group (e.g., methylcarbonyl,ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, isobutylcarbonyl,tert-butylcarbonyl, neopentylcarbonyl), (3) an optionally substitutedC₃₋₁₀ (preferably C₃₋₆) cycloalkyl-carbonyl group (e.g.,cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl,cyclohexanecarbonyl), (4) an optionally substituted C₁₋₆ alkoxy-carbonylgroup (e.g., methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,tert-butoxycarbonyl), (5) an optionally substituted C₃₋₁₀cycloalkyloxy-carbonyl group (e.g., cyclopropyloxycarbonyl), (6) anoptionally substituted C₆₋₁₄ aryl-carbonyl group (e.g., phenylcarbonyl),(7) an optionally substituted C₆₋₁₄ aryloxy-carbonyl group (e.g.,phenyloxycarbonyl), (8) an optionally substituted 5- to 14-memberedaromatic heterocyclylcarbonyl group (e.g., furylcarbonyl,thienylcarbonyl, pyrazolylcarbonyl, isoxazolylcarbonyl,pyridylcarbonyl), (9) an optionally substituted 3- to 14-memberednon-aromatic heterocyclylcarbonyl group (e.g., azetidinylcarbonyl,oxetanylcarbonyl, pyrrolidinylcarbonyl, tetrahydrofuranylcarbonyl,tetrahydropyranylcarbonyl, morpholinylcarbonyl), (10) an optionallysubstituted mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl,dimethylcarbamoyl), (11) an optionally substituted mono- or di-C₃₋₁₀cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl), (12) anoptionally substituted mono- or di-C₆₋₁₄ aryl-carbamoyl group (e.g.,phenylcarbamoyl), (13) an optionally substituted C₁₋₆ alkylsulfonylgroup (e.g., methylsulfonyl), (14) an optionally substituted C₃₋₁₀cycloalkylsulfonyl group (e.g., cyclopropylsulfonyl), (15) an optionallysubstituted C₆₋₁₄ arylsulfonyl group (e.g., phenylsulfonyl), (16) anoptionally substituted heterocyclyl-sulfonyl group (e.g.,thienylsulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, pyridylsulfonyl,dihydrochromenylsulfonyl), (17) an optionally substituted mono- ordi-C₁₋₆ alkyl-sulfamoyl group (e.g., dimethylsulfamoyl) or (18) anoptionally substituted C₁₋₆ alkyl-carbonyl-carbonyl group (e.g.,methylcarbonylcarbonyl);

R² is a C₃₋₆ cycloalkyl group (e.g., cyclobutyl, cyclopentyl,cyclohexyl) or a 3- to 6-membered saturated monocyclic non-aromaticheterocyclic group (e.g., pyrrolidinyl, piperidinyl, dioxanyl), each ofwhich is optionally substituted by 1 to 3 substituents selected from (1)deuterium, (2) a halogen atom (e.g., fluorine atom), (3) a hydroxygroup, (4) an optionally substituted C₁₋₆ alkyl group (e.g., methyl,isopropyl), (5) a C₃₋₁₀ cycloalkyl group (e.g., cyclohexyl), (6) anoptionally substituted C₁₋₆ alkoxy group (e.g., methoxy), (7) anoptionally substituted C₆₋₁₄ aryl group (e.g., phenyl), (8) a C₆₋₁₄aryloxy group (e.g., phenoxy), (9) a tri-C₁₋₆ alkylsilyl group (e.g.,tert-butyl(dimethyl)silyl) and (10) an optionally substituted 5- to14-membered aromatic heterocyclic group (e.g., pyrazolyl, thiazolyl,pyridyl, pyrimidinyl, quinazolinyl, benzothiazolyl, isoquinolinyl); and

R³ is a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl,isobutyl) optionally substituted by 1 to 3 substituents selected from ahalogen atom (e.g., fluorine atom) and a C₆₋₁₄ aryl group (e.g.,phenyl), or a mono- or di-C₁₋₆ alkylamino group (e.g., ethylamino,dimethylamino).

[Compound I-2]

Compound (I) wherein R¹ is (1) a hydrogen atom, (2) a C₁₋₆alkyl-carbonyl group (e.g., methylcarbonyl, ethylcarbonyl,propylcarbonyl, isopropylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl,neopentylcarbonyl) optionally substituted by 1 to 7 substituentsselected from a halogen atom (e.g., fluorine atom), a cyano group, ahydroxy group, a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), a C₁₋₆alkoxy group (e.g., methoxy), a C₆₋₁₄ aryl group (e.g., phenyl), a C₆₋₁₄aryloxy group (e.g., phenoxy), a 5- to 14-membered aromatic heterocyclicgroup (e.g., pyrazolyl, thiazolyl, pyrimidinyl, pyridazinyl) optionallysubstituted by an oxo group, a 5- to 14-membered aromaticheterocyclyloxy group (e.g., pyrazolyloxy) optionally substituted by 1to 3 substituents selected from a C₁₋₆ alkyl group (e.g., methyl), aC₁₋₆ alkyl-carbonyl group (e.g., methylcarbonyl), a C₁₋₆ alkoxy-carbonylgroup (e.g., methoxycarbonyl), a C₁₋₆ alkyl-carbonyloxy group (e.g.,methylcarbonyloxy), a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl), amono- or di-C₁₋₆ alkylamino group (e.g., dimethylamino), a C₁₋₆alkyl-carbonylamino group (e.g., acetylamino) and a (C₁₋₆ alkyl) (C₁₋₆alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino), (3) a C₃₋₁₀(preferably C₃₋₆) cycloalkyl-carbonyl group (e.g., cyclopropanecarbonyl,cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl)optionally substituted by 1 to 3 substituents selected from a halogenatom (e.g., fluorine atom), a cyano group, a hydroxy group, an oxo groupand a C₁₋₆ alkyl group (e.g., methyl), (4) a C₁₋₆ alkoxy-carbonyl group(e.g., methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,tert-butoxycarbonyl) optionally substituted by 1 to 6 substituentsselected from deuterium, a halogen atom (e.g., fluorine atom) and aC₆₋₁₄ aryl group (e.g., phenyl), (5) a C₃₋₁₀ cycloalkyloxy-carbonylgroup (e.g., cyclopropyloxycarbonyl) optionally substituted by 1 to 3substituents selected from a C₁₋₆ alkyl group (e.g., methyl), (6) aC₆₋₁₄ aryl-carbonyl group (e.g., phenylcarbonyl) optionally substitutedby 1 to 3 substituents selected from a halogen atom (e.g., fluorineatom, chlorine atom) and a C₆₋₁₄ aryl group (e.g., phenyl), (7) a C₆₋₁₄aryloxy-carbonyl group (e.g., phenyloxycarbonyl), (8) a 5- to14-membered aromatic heterocyclylcarbonyl group (e.g., furylcarbonyl,thienylcarbonyl, pyrazolylcarbonyl, isoxazolylcarbonyl, pyridylcarbonyl)optionally substituted by 1 to 3 substituents selected from a C₁₋₆ alkylgroup (e.g., methyl), (9) a 3- to 14-membered non-aromaticheterocyclylcarbonyl group (e.g., azetidinylcarbonyl, oxetanylcarbonyl,pyrrolidinylcarbonyl, tetrahydrofuranylcarbonyl,tetrahydropyranylcarbonyl, morpholinylcarbonyl) optionally substitutedby 1 to 3 substituents selected from an oxo group, a C₁₋₆ alkyl-carbonylgroup (e.g., methylcarbonyl), a C₁₋₆ alkoxy-carbonyl group (e.g.,tert-butoxycarbonyl) and a C₁₋₆ alkylsulfonyl group (e.g.,methylsulfonyl), (10) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl,dimethylcarbamoyl) optionally substituted by 1 to 3 substituentsselected from a halogen atom (e.g., fluorine atom), a cyano group, ahydroxy group and a C₁₋₆ alkoxy group (e.g., methoxy), (11) a mono- ordi-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl), (12) amono- or di-C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl), (13) aC₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl), (14) a C₃₋₁₀cycloalkylsulfonyl group (e.g., cyclopropylsulfonyl), (15) a C₆₋₁₄arylsulfonyl group (e.g., phenylsulfonyl) optionally substituted by 1 to3 halogen atoms (e.g., chlorine atom), (16) a heterocyclyl-sulfonylgroup (e.g., thienylsulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl,pyridylsulfonyl, dihydrochromenylsulfonyl) optionally substituted by 1to 3 substituents selected from a C₁₋₆ alkyl group (e.g., methyl), (17)a mono- or di-C₁₋₆ alkyl-sulfamoyl group (e.g., dimethylsulfamoyl) or(18) a C₁₋₆ alkyl-carbonyl-carbonyl group (e.g.,methylcarbonylcarbonyl);

R² is a C₃₋₆ cycloalkyl group (e.g., cyclobutyl, cyclopentyl,cyclohexyl) or a 3- to 6-membered saturated monocyclic non-aromaticheterocyclic group (e.g., pyrrolidinyl, piperidinyl, dioxanyl), each ofwhich is optionally substituted by 1 to 3 substituents selected from (1)deuterium, (2) a halogen atom (e.g., fluorine atom), (3) a hydroxygroup, (4) a C₁₋₆ alkyl group (e.g., methyl, isopropyl) optionallysubstituted by 1 to 3 substituents selected from a halogen atom (e.g.,fluorine atom) and a C₆₋₁₄ aryl group (e.g., phenyl), (5) a C₃₋₁₀cycloalkyl group (e.g., cyclohexyl), (6) a C₁₋₆ alkoxy group (e.g.,methoxy) optionally substituted by a C₃₋₁₀ cycloalkyl group (e.g.,cyclopropyl), (7) a C₆₋₁₄ aryl group (e.g., phenyl) optionallysubstituted by 1 to 3 substituents selected from a halogen atom (e.g.,fluorine atom, chlorine atom), a cyano group, a C₁₋₆ alkyl group (e.g.,methyl, ethyl) optionally substituted by 1 to 3 halogen atoms (e.g.,fluorine atom) and a C₁₋₆ alkoxy group (e.g., methoxy) optionallysubstituted by 1 to 3 halogen atoms (e.g., fluorine atom), (8) a C₆₋₁₄aryloxy group (e.g., phenoxy), (9) a tri-C₁₋₆ alkylsilyl group (e.g.,tert-butyl(dimethyl)silyl) and (10) a 5- to 14-membered aromaticheterocyclic group (e.g., pyrazolyl, thiazolyl, pyridyl, pyrimidinyl,quinazolinyl, benzothiazolyl, isoquinolinyl) optionally substituted by 1to 3 substituents selected from a halogen atom (e.g., fluorine atom,chlorine atom), C₁₋₆ alkyl group (e.g., methyl) and a C₁₋₆ alkoxy group(e.g., methoxy); and

R³ is a C₁₋₆ alkyl group (e.g., methyl), or a mono- or di-C₁₋₆alkylamino group (e.g., dimethylamino).

[Compound I-3]

Compound (I), wherein R¹ is (1) a C₁₋₆ alkyl-carbonyl group (e.g.,methylcarbonyl) optionally substituted by a hydroxy group, (2) a C₃₋₆cycloalkyl-carbonyl group (e.g., cyclopropanecarbonyl), (3) a C₁₋₆alkoxy-carbonyl group (e.g., methoxycarbonyl, isopropoxycarbonyl) or (4)a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g., ethylcarbamoyl);

R² is (A) a C₃₋₆ cycloalkyl group (e.g., cyclohexyl) optionallysubstituted by 1 to 3 substituents selected from (1) a C₁₋₆ alkyl group(e.g., isopropyl) and (2) a C₆₋₁₄ aryl group (e.g., phenyl) optionallysubstituted by 1 to 3 substituents selected from a halogen atom (e.g.,fluorine atom), a C₁₋₆ alkyl group (e.g., methyl) optionally substitutedby 1 to 3 halogen atoms (e.g., fluorine atom) and a C₁₋₆ alkoxy group(e.g., methoxy) or (B) a 3- to 6-membered saturated monocyclicnon-aromatic heterocyclic group (e.g., piperidinyl) optionallysubstituted by 1 to 3 substituents selected from a 5- to 14-memberedaromatic heterocyclic group (e.g., pyrimidinyl); and

R³ is a C₁₋₆ alkyl group (e.g., methyl) or a di-C₁₋₆ alkylamino group(e.g., dimethylamino).

[Compound I-4]

Compound (I), which is the compound of [7] mentioned above.

[Compound I-5]

Compound (I), wherein R¹ is

(1) a hydrogen atom,

(2) a C₁₋₆ alkyl-carbonyl group optionally substituted by 1 to 7substituents selected from (i) a halogen atom, (ii) a cyano group, (iii)a hydroxy group, (iv) a C₃₋₁₀ cycloalkyl group, (v) a C₁₋₆ alkoxy group,(vi) a C₆₋₁₄ aryl group, (vii) a C₆₋₁₄ aryloxy group, (viii) a 5- to14-membered aromatic heterocyclic group optionally substituted by an oxogroup, (ix) a 5- to 14-membered aromatic heterocyclyloxy groupoptionally substituted by 1 to 3 C₁₋₆ alkyl groups, (x) a C₁₋₆alkyl-carbonyl group, (xi) a C₁₋₆ alkoxy-carbonyl group, (xii) a C₁₋₆alkyl-carbonyloxy group, (xiii) a C₁₋₆ alkylsulfonyl group, (xiv) amono- or di-C₁₋₆ alkylamino group, (xv) a C₁₋₆ alkyl-carbonylamino groupand (xvi) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl)amino group,(3) a C₃₋₁₀ cycloalkyl-carbonyl group optionally substituted by 1 to 3substituents selected from a halogen atom, a cyano group, a hydroxygroup, an oxo group and a C₁₋₆ alkyl group,(4) a C₁₋₆ alkoxy-carbonyl group optionally substituted by 1 to 6substituents selected from deuterium, a halogen atom and a C₆₋₁₄ arylgroup,(5) a C₃₋₁₀ cycloalkyloxy-carbonyl group optionally substituted by 1 to3 substituents selected from a C₁₋₆ alkyl group,(6) a C₆₋₁₄ aryl-carbonyl group optionally substituted by 1 to 3substituents selected from a halogen atom and a C₆₋₁₄ aryl group,(7) a C₆₋₁₄ aryloxy-carbonyl group,(8) a 5- to 14-membered aromatic heterocyclylcarbonyl group optionallysubstituted by 1 to 3 substituents selected from a C₁₋₆ alkyl group,(9) a 3- to 14-membered non-aromatic heterocyclylcarbonyl groupoptionally substituted by 1 to 3 substituents selected from an oxogroup, a C₁₋₆ alkyl-carbonyl group, a C₁₋₆ alkoxy-carbonyl group and aC₁₋₆ alkylsulfonyl group,(10) a mono- or di-C₁₋₆ alkyl-carbamoyl group optionally substituted by1 to 3 substituents selected from a halogen atom, a cyano group, ahydroxy group and a C₁₋₆ alkoxy group,(11) a mono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group,(12) a mono- or di-C₆₋₁₄ aryl-carbamoyl group,(13) a C₁₋₆ alkylsulfonyl group,(14) a C₃₋₁₀ cycloalkylsulfonyl group,(15) a C₆₋₁₄ arylsulfonyl group optionally substituted by 1 to 3 halogenatoms,(16) a heterocyclyl-sulfonyl group optionally substituted by 1 to 3substituents selected from a C₁₋₆ alkyl group,(17) a mono- or di-C₁₋₆ alkyl-sulfamoyl group or(18) a C₁₋₆ alkyl-carbonyl-carbonyl group;

R² is a C₃₋₆ cycloalkyl group or a 3- to 6-membered saturated monocyclicnon-aromatic heterocyclic group, each of which is optionally substitutedby 1 to 3 substituents selected from

(1) deuterium,

(2) a halogen atom,

(3) a hydroxy group,

(4) a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituentsselected from a halogen atom and a C₆₋₁₄ aryl group,

(5) a C₃₋₁₀ cycloalkyl group,

(6) a C₁₋₆ alkoxy group optionally substituted by a C₃₋₁₀ cycloalkylgroup,

(7) a C₆₋₁₄ aryl group optionally substituted by 1 to 3 substituentsselected from a halogen atom, a cyano group, a C₁₋₆ alkyl groupoptionally substituted by 1 to 3 halogen atoms, a C₁₋₆ alkoxy groupoptionally substituted by 1 to 3 halogen atoms and a hydroxy group,(8) a C₆₋₁₄ aryloxy group,(9) a tri-C₁₋₆ alkylsilyloxy group,(10) a 5- to 14-membered aromatic heterocyclic group optionallysubstituted by 1 to 3 substituents selected from a halogen atom, a C₁₋₆alkyl group and a C₁₋₆ alkoxy group and(11) a C₆₋₁₄ aryl-carbonyl group; and

R³ is a C₁₋₆ alkyl group, or a mono- or di-C₁₋₆ alkylamino group.

[Compound I-6]

Compound (I), which is the compound of [8] mentioned above.

[Compound I-7]

Compound (I), wherein R¹ is

(1) a hydrogen atom,

(2) a C₁₋₆ alkyl-carbonyl group optionally substituted by 1 to 7substituents selected from (i) a halogen atom, (ii) a cyano group, (iii)a hydroxy group, (iv) a cyclopropyl group, (v) a C₁₋₆ alkoxy group, (vi)a phenyl group, (vii) a phenoxy group, (viii) a pyrazolyl group, athiazolyl group, a pyrimidinyl group or a pyridazinyl group, each ofwhich is optionally substituted by an oxo group, (ix) a pyrazolyloxygroup optionally substituted by 1 to 3 substituents selected from a C₁₋₆alkyl group, (x) a C₁₋₆ alkyl-carbonyl group, (xi) a C₁₋₆alkoxy-carbonyl group, (xii) a C₁₋₆ alkyl-carbonyloxy group, (xiii) aC₁₋₆ alkylsulfonyl group, (xiv) a mono- or di-C₁₋₆ alkylamino group,(xv) a C₁₋₆ alkyl-carbonylamino group and (xvi) a (C₁₋₆ alkyl) (C₁₋₆alkyl-carbonyl)amino group, (3) a cyclopropanecarbonyl group, acyclobutanecarbonyl group, a cyclopentanecarbonyl group or acyclohexanecarbonyl group, each of which is optionally substituted by 1to 3 substituents selected from a halogen atom, a cyano group, a hydroxygroup, an oxo group and a C₁₋₆ alkyl group,(4) a C₁₋₆ alkoxy-carbonyl group optionally substituted by 1 to 6substituents selected from deuterium, a halogen atom and a phenyl group,(5) a cyclopropyloxycarbonyl group optionally substituted by 1 to 3substituents selected from a C₁₋₆ alkyl group,(6) a phenylcarbonyl group optionally substituted by 1 to 3 substituentsselected from a halogen atom and a phenyl group,(7) a phenyloxycarbonyl group,(8) a furylcarbonyl group, a thienylcarbonyl group, a pyrazolylcarbonylgroup, an isoxazolylcarbonyl group or a pyridylcarbonyl group, each ofwhich is optionally substituted by 1 to 3 C₁₋₆ alkyl groups,(9) an azetidinylcarbonyl group, an oxetanylcarbonyl group, apyrrolidinylcarbonyl group, a tetrahydrofuranylcarbonyl group, atetrahydropyranylcarbonyl group or a morpholinylcarbonyl group, each ofwhich is optionally substituted by 1 to 3 substituents selected from anoxo group, a C₁₋₆ alkyl-carbonyl group, a C₁₋₆ alkoxy-carbonyl group anda C₁₋₆ alkylsulfonyl group,(10) a mono- or di-C₁₋₆ alkyl-carbamoyl group optionally substituted by1 to 3 substituents selected from a halogen atom, a cyano group, ahydroxy group and a C₁₋₆ alkoxy group,(11) a cyclopropylcarbamoyl group,(12) a phenylcarbamoyl group,(13) a C₁₋₆ alkylsulfonyl group,(14) a cyclopropylsulfonyl group,(15) a phenylsulfonyl group optionally substituted by 1 to 3 halogenatoms,(16) a thienylsulfonyl group, a pyrazolylsulfonyl group, animidazolylsulfonyl group, a pyridylsulfonyl group or adihydrochromenylsulfonyl group, each of which is optionally substitutedby 1 to 3 C₁₋₆ alkyl groups,(17) a dimethylsulfamoyl group or(18) a C₁₋₆ alkyl-carbonyl-carbonyl group;

R² is a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, apyrrolidinyl group, a piperidinyl group or a dioxanyl group, each ofwhich is optionally substituted by 1 to 3 substituents selected from

(1) deuterium,

(2) a halogen atom,

(3) a hydroxy group,

(4) a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituentsselected from a halogen atom and a phenyl group,

(5) a cyclohexyl group,

(6) a C₁₋₆ alkoxy group optionally substituted by a cyclopropyl group,

(7) a phenyl group optionally substituted by 1 to 3 substituentsselected from a halogen atom, a cyano group, a C₁₋₆ alkyl groupoptionally substituted by 1 to 3 halogen atoms, a C₁₋₆ alkoxy groupoptionally substituted by 1 to 3 halogen atoms and a hydroxy group,(8) a phenoxy group,(9) a tri-C₁₋₆ alkylsilyloxy group,(10) a pyrazolyl group, a thiazolyl group, a pyridyl group, apyrimidinyl group, a quinazolinyl group, a benzothiazolyl group or anisoquinolinyl group, each of which is optionally substituted by 1 to 3substituents selected from a halogen atom, a C₁₋₆ alkyl group and a C₁₋₆alkoxy group, and(11) a benzoyl group; and

R³ is a C₁₋₆ alkyl group, or a mono- or di-C₁₋₆ alkylamino group.

[Compound I-8]

Compound (I), which is the compound of [9] mentioned above.

[Compound I-9]

Compound (I), which is the compound of [10] mentioned above.

[Compound I-10]

Compound (I), wherein R¹ is a C₁₋₆ alkoxy-carbonyl group;

R² is a cyclohexyl group optionally substituted by a phenyl group; and

R³ is a C₁₋₆ alkyl group.

[Compound I-11]

Compound (I), wherein R¹ is a C₁₋₆ alkyl-carbonyl group optionallysubstituted by a hydroxy group;

R² is a cyclohexyl group optionally substituted by a phenyl groupoptionally substituted by 1 to 3 halogen atoms; and

R³ is a C₁₋₆ alkyl group.

[Compound I-12]

Compound (I), wherein R¹ is a mono- or di-C₁₋₆ alkyl-carbamoyl group;

R² is a cyclohexyl group optionally substituted by a C₁₋₆ alkyl group;and

R³ is a C₁₋₆ alkyl group.

Specific examples of compound (I) include the compounds of thebelow-mentioned Examples 1-372, of which

(2R,3S)—N-ethyl-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)-3-((methylsulfonyl)amino)piperidine-1-carboxamide(Example 2),

N-((2R,3S)-1-acetyl-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(Example 4),

methyl(2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate(Example 5),

N-((2R,3S)-1-acetyl-2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(Example 8),

methyl(2R,3S)-2-(((cis-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate(Example 11),

N-((2R,3S)-1-acetyl-2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(Example 14),

N-((2R,3S)-1-(cyclopropylcarbonyl)-2-(((cis-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(Example 16),

N-((2R,3S)-1-acetyl-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(Example 19),

methyl(2R,3S)-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate(Example 20),

N-((2R,3S)-1-acetyl-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(Example 22),

N-((2R,3S)-1-acetyl-2-(((cis-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(Example 24),

N-((2R,3S)-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)-1-glycoloylpiperidin-3-yl)methanesulfonamide(Example 25),

N-((2R,3S)-1-(cyclopropylcarbonyl)-2-(((cis-4-(2-methoxyphenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(Example 28),

isopropyl(2R,3S)-3-((dimethylsulfamoyl)amino)-2-(((1-(pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)piperidine-1-carboxylate(Example 29),

(2R,3S)—N-ethyl-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxamide(Example 30),

N-((2R,3S)-1-(cyclopropylcarbonyl)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(Example 31),

methyl(2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)piperidine-1-carboxylate(Example 32),

N-((2R,3S)-2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(Example 7),

N-((2R,3S)-2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(Example 13),

N-(2-(((cis-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide(Example 15), and

N-((2R,3S)-1-glycoloyl-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(Example 340) are preferable.

As a salt of a compound represented by the formula (I), apharmacologically acceptable salt is preferable, and examples of suchsalt include a salt with inorganic base, a salt with organic base, asalt with inorganic acid, a salt with organic acid, a salt with basic oracidic amino acid and the like.

Preferable examples of the salt with inorganic base include alkali metalsalts such as sodium salt, potassium salt and the like, alkaline earthmetal salts such as calcium salt, magnesium salt and the like, aluminumsalt, ammonium salt and the like.

Preferable examples of the salt with organic base include salts withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine,tromethamine[tris(hydroxymethyl)methylamine], tert-butylamine,cyclohexylamine, benzylamine, dicyclohexylamine,N,N-dibenzylethylenediamine and the like.

Preferable examples of the salt with inorganic acid include salts withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like.

Preferable examples of the salt with organic acid include salts withformic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaricacid, oxalic acid, tartaric acid, maleic acid, citric acid, succinicacid, malic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid and the like.

Preferable examples of the salt with basic amino acid include salts witharginine, lysine, ornithine and the like.

Preferable examples of the salt with acidic amino acid include saltswith aspartic acid, glutamic acid and the like.

Compound (I) may be used as a prodrug. A prodrug of the compound (I)means a compound which is converted to the compound (I) of the presentinvention with a reaction due to an enzyme, an gastric acid, etc. underthe physiological condition in the living body, that is, a compoundwhich is converted to the compound (I) of the present invention withoxidation, reduction, hydrolysis, etc. according to an enzyme; acompound which is converted to the compound (I) of the present inventionby hydrolysis etc. due to gastric acid, etc.

A prodrug of compound (I) may be a compound obtained by subjecting anamino group in compound (I) to an acylation, alkylation orphosphorylation (e.g., a compound obtained by subjecting an amino groupin compound (I) to an eicosanoylation, alanylation,pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylationand tert-butylation, etc.); a compound obtained by subjecting a hydroxygroup in compound (I) to an acylation, alkylation, phosphorylation orboration (e.g., a compound obtained by subjecting an hydroxy group incompound (I) to an acetylation, palmitoylation, propanoylation,pivaloylation, succinylation, fumarylation, alanylation,dimethylaminomethylcarbonylation, etc.); a compound obtained bysubjecting a carboxyl group in compound (I) to an esterification oramidation (e.g., a compound obtained by subjecting a carboxyl group incompound (I) to an ethyl esterification, phenyl esterification,carboxymethyl esterification, dimethylaminomethyl esterification,pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification,phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification, cyclohexyloxycarbonylethyl esterification andmethylamidation, etc.) and the like. Any of these compounds can beproduced from compound (I) by a method known per se.

A prodrug for compound (I) may also be one which is converted intocompound (I) under a physiological condition, such as those described inIYAKUHIN no KAIHATSU (Development of Pharmaceuticals), Vol. 7, Design ofMolecules, p.163-198, Published by HIROKAWA SHOTEN (1990).

In the present specification, a prodrug may form a salt, and as suchsalt, those exemplified as a salt of the compound represented by theaforementioned formula (I) can be mentioned.

Compound (I) may be labeled with an isotope (e.g., ³H, ¹³C, ¹⁴C, ¹⁸F,³⁵S, ¹²⁵I) and the like.

Compound (I) labeled with or substituted by an isotope can be used, forexample, as a tracer used for Positron Emission Tomography (PET) (PETtracer), and is useful in the field of medical diagnosis and the like.

Furthermore, compound (I) may be a hydrate or a non-hydrate, or anon-solvate (e.g., anhydride), or a solvate (e.g., hydrate).

Compound (I) also encompasses a deuterium conversion form wherein ¹H isconverted to ²H(D).

Furthermore, compound (I) may be a pharmaceutically acceptable cocrystalor cocrystal salt. The cocrystal or cocrystal salt means a crystallinesubstance constituted with two or more special solids at roomtemperature, each having different physical properties (e.g., structure,melting point, melting heat, hygroscopicity, solubility and stability).The cocrystal or cocrystal salt can be produced by a cocrystallizationmethod known per se.

Compound (I) or a prodrug thereof (hereinafter sometimes to be simplyabbreviated as the compound of the present invention) is low in itstoxicity and can be used as it is or in the form of a pharmaceuticalcomposition (also referred to as a medicament) by mixing with apharmacologically acceptable carrier etc. to mammals (e.g., human,mouse, rat, rabbit, dog, cat, bovine, horse, swine, monkey) as an agentfor the prophylaxis or treatment of various diseases mentioned below.

As pharmacologically acceptable carriers, various organic or inorganiccarrier substances conventionally used as preparation materials can beused. These are incorporated as excipient, lubricant, binder anddisintegrant for solid preparations; or solvent, solubilizing agent,suspending agent, isotonicity agent, buffer and soothing agent forliquid preparations; and the like; and preparation additives such aspreservative, antioxidant, colorant, sweetening agent and the like canbe added as necessary.

Preferable examples of the excipient include lactose, sucrose,D-mannitol, D-sorbitol, starch, gelatinated starch, dextrin, crystallinecellulose, low-substituted hydroxypropylcellulose, sodiumcarboxymethylcellulose, gum arabic, pullulan, light anhydrous silicicacid, synthetic aluminum silicate and magnesium alumino metasilicate.

Preferable examples of the lubricant include magnesium stearate, calciumstearate, talc and colloidal silica.

Preferable examples of the binder include gelatinated starch, sucrose,gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodiumcarboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol,trehalose, dextrin, pullulan, hydroxypropylcellulose,hydroxypropylmethylcellulose and polyvinylpyrrolidone.

Preferable examples of the disintegrant include lactose, sucrose,starch, carboxymethylcellulose, calcium carboxymethylcellulose,croscarmellose sodium, sodium carboxymethyl starch, light anhydroussilicic acid and low-substituted hydroxypropylcellulose.

Preferable examples of the solvent include water for injection,physiological brine, Ringer's solution, alcohol, propylene glycol,polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil.

Preferable examples of the solubilizing agent include polyethyleneglycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate,ethanol, trisaminomethane, cholesterol, triethanolamine, sodiumcarbonate, sodium citrate, sodium salicylate and sodium acetate.

Preferable examples of the suspending agent include surfactants such asstearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate,lecithin, benzalkonium chloride, benzethonium chloride, glycerolmonostearate and the like; hydrophilic polymers such as poly(vinylalcohol), polyvinylpyrrolidone, carboxymethylcellulose sodium,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and the like, polysorbates; and polyoxyethylenehydrogenated castor oil.

Preferable examples of the isotonicity agent include sodium chloride,glycerol, D-mannitol, D-sorbitol and glucose.

Preferable examples of the buffer include buffers of phosphate, acetate,carbonate, citrate etc.

Preferable examples of the soothing agent include benzyl alcohol.

Preferable examples of the preservative include p-oxybenzoate esters,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid andsorbic acid.

Preferable examples of the antioxidant include sulfite salts andascorbate salts.

Preferable examples of the colorant include aqueous food tar colors(e.g., food colors such as Food Color Red Nos. 2 and 3, Food ColorYellow Nos. 4 and 5, Food Color Blue Nos. 1 and 2 and the like foodcolors), water insoluble lake dyes (e.g., aluminum salt of theaforementioned aqueous food tar color), natural dyes (e.g., β-carotene,chlorophyll, red iron oxide) and the like.

Preferable examples of the sweetening agent include saccharin sodium,dipotassium glycyrrhizinate, aspartame and stevia.

Examples of the dosage form of the aforementioned pharmaceuticalcomposition include oral preparations such as tablet (includingsugar-coated tablet, film-coated tablet, sublingual tablet, orallydisintegrating tablet), capsule (including soft capsule, microcapsule),granule, powder, troche, syrup, emulsion, suspension, films (e.g.,orally disintegrable films) and the like; and parenteral agents such asinjection (e.g., subcutaneous injection, intravenous injection,intramuscular injection, intraperitoneal injection, drip infusion),external preparation (e.g., dermal preparation, ointment), suppository(e.g., rectal suppository, vaginal suppository), pellet, nasalpreparation, pulmonary preparation (inhalant), eye drop and the like,which can be respectively safely administered orally or parenterally(e.g., topical, rectal, intravenous administration).

These preparations may be a release control preparation (e.g.,sustained-release microcapsule) such as an immediate-releasepreparation, a sustained-release preparation and the like.

The pharmaceutical composition can be produced according to a methodconventionally used in the field of pharmaceutical the formulation, forexample, the method described in the Japanese Pharmacopoeia, and thelike.

While the content of the compound of the present invention in thepharmaceutical composition of the present invention varies depending onthe dosage form, dose of the compound of the present invention and thelike, it is, for example, about 0.1 to 100 wt %.

When an oral preparation is produced, coating may be applied wherenecessary for the purpose of taste masking, enteric solubility orsustainability.

Examples of the coating base used for coating include sugar coatingbase, water-soluble film coating base, enteric film coating base, andsustained-release film coating base.

As the sugar coating base, sucrose is used, and one or more kindsselected from talc, precipitated calcium carbonate, gelatin, gum arabic,pullulan, carnauba wax and the like may be further used in combination.

Examples of the water-soluble film coating base include cellulosepolymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose,hydroxyethylcellulose, methylhydroxyethylcellulose and the like;synthetic polymers such as polyvinyl acetal diethylaminoacetate,aminoalkylmethacrylate copolymer E [Eudragit E (trade name)],polyvinylpyrrolidone and the like; and polysaccharides such as pullulanand the like.

Examples of the enteric film coating base include cellulose polymerssuch as hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetate succinate,carboxymethylethylcellulose, cellulose acetate phthalate and the like;acrylic acid polymers such as methacrylic acid copolymer L [Eudragit L(trade name)], methacrylic acid copolymer LD [Eudragit L-30D-55 (tradename)], methacrylic acid copolymer S [Eudragit S (trade name)] and thelike; and naturally-occurring substances such as shellac and the like.

Examples of the sustained-release film coating base include cellulosepolymers such as ethylcellulose and the like; and acrylic acid polymerssuch as aminoalkylmethacrylate copolymer RS [Eudragit RS (trade name)],ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE(trade name)] and the like.

Two or more kinds of the above-mentioned coating bases may be used in amixture at an appropriate ratio. In addition, for example, lightshielding agents such as titanium oxide, red ferric oxide and the likemay also be used during coating.

Since the compound of the present invention shows low toxicity (e.g.,acute toxicity, chronic toxicity, genetic toxicity, reproductivetoxicity, cardiotoxicity, carcinogenicity) and less side effects, it canbe used as a prophylactic or therapeutic agent, or diagnostic agent forvarious diseases in mammals (e.g., human, bovine, horse, dog, cat,monkey, mouse, rat).

Orexin type 2 receptors have been considered to be involved in a widerange of biological functions. This suggests that this receptor plays arole in diverse disease processes in humans or other species. Thecompound of the present invention is useful for treating, preventing, orameliorating the risk of one or more of the following symptoms ordiseases of various neurological and psychiatric diseases associatedwith one or more orexin type 2 receptors. That is, narcolepsy,idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsysyndrome accompanied by narcolepsy-like symptoms, hypersomnia syndromeaccompanied by daytime hypersomnia (e.g., Kleine Levin syndrome, majordepression with hypersomnia, Lewy body dementia, Parkinson's disease,progressive supranuclear paralysis, Prader-Willi syndrome, Mobiussyndrome, hypoventilation syndrome, Niemann-Pick disease type C, braincontusion, cerebral infarction, brain tumor, muscular dystrophy,multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barresyndrome, Rasmussen's encephalitis, Wernicke's encephalitis, limbicencephalitis, Hashimoto's encephalopathy), coma, loss of consciousness,obesity (e.g., malignant mastocytosis, exogenous obesity, hyperinsulinarobesity, hyperplasmic obesity, hypop hyseal adiposity, hypoplasmicobesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity,infantile obesity, upper body obesity, alimentary obesity, hypogonadalobesity, systemic mastocytosis, simple obesity, central obesity),insulin resistance syndrome, Alzheimer, disturbance of consciousnesssuch as coma and the like, side effects and complications due toanesthesia, sleep disturbance, sleep problem, insomnia, Intermittentsleep, nocturnal myoclonus, REM sleep interruption, jet lag, jet lagsyndrome, sleep disorder of alternating worker, sleep disorder, nightterror, depression, major depression, sleepwalking disease, enuresis,sleep disorder, Alzheimer's dusk, diseases associated with circadianrhythm, fibromyalgia, condition arising from decline in the quality ofsleep, overeating, obsessive compulsive eating disorder, obesity-relateddisease, hypertension, diabetes, elevated plasma insulin concentrationand insulin resistance, hyperlipidemia, hyperlipemia, endometrialcancer, breast cancer, prostate cancer, colorectal cancer, cancer,osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones,cardiac disease, abnormal heartbeat, arrhythmia, myocardial infarction,congestive cardiac failure, cardiac failure, coronary heart disease,cardiovascular disorder, sudden death, polycysticovarian disease,craniopharingioma, Prader-Willi syndrome, Froelich's syndrome, growthhormone deficient, normal mutant short stature, Turner's syndrome,children suffering from acute lymphoblastic leukemia, syndrome X,reproductive hormone abnormality, declining fertility, infertility, malegonadal function decline, sexual and reproductive dysfunction such asfemale male hirsutism, fetal defects associated with pregnant womenobesity, gastrointestinal motility disorders such as obesity-relatedgastroesophageal reflux, obesity hypoventilation syndrome (Pickwicksyndrome), respiratory diseases such as dyspnea, inflammation such assystemic inflammation of the vascular system, arteriosclerosis,hypercholesterolemia, hyperuricemia, lower back pain, gall bladderdisease, gout, kidney cancer, risk of secondary outcomes of obesity,such as lowering the risk of left ventricular hypertrophy, migrainepain, headache, neuropathic pain, Parkinson's disease, psychosis,schizophrenia, facial flushing, night sweats, diseases of thegenital/urinary system, diseases related to sexual function orfertility, dysthymic disorder, bipolar disorder, bipolar I disorder,bipolar II disorder, cyclothymic disorder, acute stress disorder,agoraphobia, generalized anxiety disorder, obsessive disorder, panicattack, panic disorder, posttraumatic stress disorder, separationanxiety disorder, social phobia, anxiety disorder, acute neurologicaland psychiatric disorders such as cardiac bypass surgery andpost-transplant cerebral deficit, stroke, ischemic stroke, cerebralischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiacarrest, hypoglycemic nerve injury, Huntington's chorea, amyotrophiclateral sclerosis, multiple sclerosis, eye damage, retinopathy,cognitive impairment, muscle spasm, tremor, epilepsy, disordersassociated with muscle spasticity, delirium, amnestic disorder,age-related cognitive decline, schizoaffective disorder, delusionaldisorder, drug addiction, dyskinesia, chronic fatigue syndrome, fatigue,medication-induced Parkinsonism syndrome, Jill-do La Tourette'ssyndrome, chorea, myoclonus, tic, restless legs syndrome, dystonia,dyskinesia, attention deficit hyperactivity disorder (ADHD), behaviordisorder, urinary incontinence, withdrawal symptoms, trigeminalneuralgia, hearing loss, tinnitus, nerve damage, retinopathy, maculardegeneration, vomiting, cerebral edema, pain, bone pain, arthralgia,toothache, cataplexy, and traumatic brain injury (TBI).

Particularly, the compound of the present invention is useful as atherapeutic or prophylactic drug for narcolepsy, idiopathic hypersomnia,hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied bynarcolepsy-like symptoms, hypersomnia syndrome accompanied by daytimehypersomnia (e.g., Parkinson's disease, Guillain-Barre syndrome andKleine Levin syndrome), Alzheimer, obesity, insulin resistance syndrome,cardiac failure, diseases related to bone loss, sepsis, disturbance ofconsciousness such as coma and the like, side effects and complicationsdue to anesthesia, and the like, or anesthetic antagonist.

While the dose of the compound of the present invention varies dependingon the subject of administration, administration route, target disease,symptom and the like, for example, when the compound of the presentinvention is administered orally or parenterally to an adult patient,its dose is for example, about 0.01 to 100 mg/kg body weight per dose,preferably 0.1 to 50 mg/kg body weight per dose and more preferably 0.5to 20 mg/kg body weight per dose. This amount is desirably administeredin one to 3 portions daily.

The compound of the present invention can be used in combination withother drugs (hereinafter to be abbreviated as concomitant drug).

By combining the compound of the present invention and a concomitantdrug, a superior effect, for example,

(1) the dose can be reduced as compared to single administration of thecompound of the present invention or a concomitant drug,

(2) the drug to be combined with the compound of the present inventioncan be selected according to the condition of patients (mild case,severe case and the like),

(3) the period of treatment can be set longer by selecting a concomitantdrug having different action and mechanism from the compound of thepresent invention,

(4) a sustained treatment effect can be designed by selecting aconcomitant drug having different action and mechanism from the compoundof the present invention,

(5) a synergistic effect can be afforded by a combined use of thecompound of the present invention and a concomitant drug, and the like,can be achieved.

In the present specification, the compound of the present invention anda concomitant drug used in combination are referred to as the“combination agent of the present invention”.

When using the combination agent of the present invention, theadministration time of the compound of the present invention and theconcomitant drug is not restricted, and the compound of the presentinvention or a pharmaceutical composition thereof, or the concomitantdrug or a pharmaceutical composition thereof can be administered to anadministration subject simultaneously, or may be administered atdifferent times. The dosage of the concomitant drug may be determinedaccording to the dose clinically used, and can be appropriately selecteddepending on an administration subject, administration route, disease,combination and the like.

The administration mode of the combination agent of the presentinvention and the concomitant drug is not particularly limited, and thecompound of the present invention and the concomitant drug only need tobe combined on administration. Examples of such administration modeinclude the following: (1) administration of a single preparationobtained by simultaneously processing the compound of the presentinvention and the concomitant drug, (2) simultaneous administration oftwo kinds of preparations of the compound of the present invention andthe concomitant drug, which have been separately produced, by the sameadministration route, (3) administration of two kinds of preparations ofthe compound of the present invention and the concomitant drug, whichhave been separately produced, by the same administration route in astaggered manner, (4) simultaneous administration of two kinds ofpreparations of the compound of the present invention and theconcomitant drug, which have been separately produced, by differentadministration routes, (5) administration of two kinds of preparationsof the compound of the present invention and the concomitant drug, whichhave been separately produced, by different administration routes in astaggered manner (e.g., administration in the order of the compound ofthe present invention and the concomitant drug, or in the reverse order)and the like.

The dose of the concomitant drug can be appropriately determined basedon the dose employed in clinical situations. The mixing ratio of thecompound of the present invention and a concomitant drug can beappropriately determined depending on the administration subject,administration route, target disease, symptom, combination and the like.

For example, the content of the compound of the present invention in thecombination agent of the present invention differs depending on the formof a preparation, and usually from about 0.01 to about 100 wt %,preferably from about 0.1 to about 50 wt %, further preferably fromabout 0.5 to about 20 wt %, based on the whole preparation.

The content of the concomitant drug in the combination agent of thepresent invention differs depending on the form of a preparation, andusually from about 0.01 to about 100 wt %, preferably from about 0.1 toabout 50 wt %, further preferably from about 0.5 to about 20 wt %, basedon the whole preparation.

The content of additives such as a carrier and the like in thecombination agent of the present invention differs depending on the formof a preparation, and usually from about 1 to about 99.99 wt %,preferably from about 10 to about 90 wt %, based on the preparation.

Similar contents may be employed even when the compound of the presentinvention and a concomitant drug are separately formulated intopreparations.

Examples of the concomitant drug include, but are not limited to, thefollowing. A therapeutic drug for narcolepsy (e.g., methylphenidate,amphetamine, pemoline, phenelzine, protriptyline, sodium oxybate,modafinil, caffeine), antiobesity drug (amphetamine, benzfetamine,bromocriptine, bupropion, diethylpropion, exenatide, fenfluramine,liothyronine, liraglutide, mazindol, methamphetamine, octreotide,octreotide, orlistat, phendimetrazine, phendimetrazine, phenmetrazine,phentermine, Qnexa (registered trade mark), phenylpropanolamine,pramlintide, propylhexedrine, recombinant leptin, sibutramine,topiramate, zimelidine, zonisamide, Lorcaserin, metformin),acetylcholine esterase inhibitor (e.g., donepezil, rivastigmine,galanthamine, zanapezil, idebenone, tacrine), antidementia agent (e.g.,memantine), inhibitor of β amyloid protein production, secretion,accumulation, aggregation and/or deposition, β secretase inhibitor(e.g., 6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin,6-(4-biphenylyl)methoxy-2-(N,N-dimethylamino)methyltetralin,6-(4-biphenylyl)methoxy-2-(N,N-dipropylamino)methyltetralin,2-(N,N-dimethylamino)methyl-6-(4′-methoxybiphenyl-4-yl)methoxytetralin,6-(4-biphenylyl)methoxy-2-[2-(N,N-diethylamino)ethyl]tetralin,2-[2-(N,N-dimethylamino)ethyl]-6-(4′-methylbiphenyl-4-yl)methoxytetralin,2-[2-(N,N-dimethylamino)ethyl]-6-(4′-methoxybiphenyl-4-yl)methoxytetralin,6-(2′,4′-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin,6-[4-(1,3-benzodioxol-5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin,6-(3′,4′-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin,an optically active form thereof, a salt thereof and a hydrate thereof,OM99-2 (WO01/00663)), γ secretase inhibitor, β amyloid proteinaggregation inhibitor (e.g., PTI-00703, ALZHEMED (NC-531), PPI-368(National Publication of International Patent Application No.11-514333), PPI-558 (National Publication of International PatentApplication No. 2001-500852), SKF-74652 (Biochem. J. (1999), 340(1),283-289)), β amyloid vaccine, β amyloid-degrading enzyme and the like,brain function enhancer (e.g., aniracetam, nicergoline), therapeuticdrug for Parkinson's disease [(e.g., dopamine receptor agonist (e.g.,L-DOPA, bromocriptine, pergolide, talipexole, pramipexole, cabergoline,amantadine), monoamine oxidase enzyme (MAO) inhibitor (e.g., deprenyl,selegiline, remacemide, riluzole), anticholinergic agent (e.g.,trihexyphenidyl, biperiden), COMT inhibitor (e.g., entacapone)],therapeutic drug for amyotrophic lateral sclerosis (e.g., riluzole etc.,neurotrophic factor), therapeutic drug for abnormal behavioraccompanying progress of dementia, wandering and the like (e.g.,sedative, anti-anxiety drug), apoptosis inhibitor (e.g., CPI-1189,IDN-6556, CEP-1347), neuronal differentiation ●regenerate promoter(e.g., leteprinim, xaliproden; SR-57746-A), SB-216763, Y-128, VX-853,prosaptide,5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline,5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindoline,6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]isoindoleand an optically active form, salt or hydrate thereof), non-steroidalantiinflammatory agents (meloxicam, tenoxicam, indomethacin, ibuprofen,celecoxib, rofecoxib, aspirin, indomethacin etc.), steroid drug(dexamethasone, hexestrol, cortisone acetate etc.), disease-modifyinganti-rheumatic drug (DMARDs), anti-cytokine drug (e.g., TNF inhibitor,MAP kinase inhibitor), therapeutic agent for incontinence, frequenturination (e.g., flavoxate hydrochloride, oxybutynin hydrochloride,propiverine hydrochloride), phosphodiesterase inhibitor (e.g.,sildenafil (citrate)), dopamine agonist (e.g., apomorphine),antiarrhythmic drugs (e.g., mexiletine), sex hormone or a derivativethereof (e.g., progesterone, estradiol, estradiol benzoate), therapeuticagent for osteoporosis (e.g., alfacalcidol, calcitriol, elcatonin,calcitonin salmon, estriol, ipriflavone, pamidronate disodium,alendronate sodium hydrate, incadronate disodium), parathyroid hormone(PTH), calcium receptor antagonists, therapeutic drug for insomnia(e.g., benzodiazepines medicament, non-benzodiazepines medicament,melatonin agonist, orexin receptor antagonists), therapeutic drug forschizophrenia (e.g., typical antipsychotic agents such as haloperidoland the like; atypical antipsychotic agents such as clozapine,olanzapine, risperidone, aripiprazole and the like; medicament acting onmetabotropic glutamate receptor or ion channel conjugated-type glutamatereceptor; phosphodiesterase inhibitor), benzodiazepines medicament(chlordiazepoxide, diazepam, potassium clorazepate, lorazepam,clonazepam, alprazolam etc.), L-type calcium channel inhibitor(pregabalin etc.), tricyclic or tetracyclic antidepressant (imipraminehydrochloride, amitriptyline hydrochloride, desipramine hydrochloride,clomipramine hydrochloride etc.), selective serotonin reuptake inhibitor(fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrobromide,sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalateetc.), serotonin-noradrenaline reuptake inhibitor (venlafaxinehydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochlorideetc.), noradrenaline reuptake inhibitor (reboxetine mesylate etc.),mirtazapine, trazodone hydrochloride, nefazodone hydrochloride,bupropion hydrochloride, setiptiline maleate, 5-HT_(1A) agonist,(buspirone hydrochloride, tandospirone citrate, osemozotan hydroclorideetc.), 5-HT_(2A) antagonist, 5-HT_(2A) inverse agonist, 5-HT₃ antagonist(cyamemazine etc.), heart non-selective β inhibitor (propranololhydrochloride, oxprenolol hydrochloride etc.), histamine H₁ antagonist(hydroxyzine hydrochloride etc.), CRF antagonist, other antianxiety drug(meprobamate etc.), tachykinin antagonist (MK-869, saredutant etc.),medicament that acts on metabotropic glutamate receptor, CCK antagonist,β3 adrenaline antagonist (amibegron hydrochloride etc.), GAT-1 inhibitor(tiagabine hydrochloride etc.), N-type calcium channel inhibitor,carbonic anhydrase II inhibitor, NMDA glycine moiety agonist, NMDAantagonist (memantine etc.), peripheral benzodiazepine receptor agonist,vasopressin antagonist, vasopressin V1b antagonist, vasopressin V1aantagonist, phosphodiesterase inhibitor, opioid antagonist, opioidagonist, uridine, nicotinic acid receptor agonist, thyroid hormone (T3,T4), TSH, TRH, MAO inhibitor (phenelzine sulfate, tranylcyprominesulfate, moclobemide etc.), COMT inhibitor (entacapone etc.),therapeutic drug for bipolar disorder (lithium carbonate, sodiumvalproate, lamotrigine, riluzole, felbamate etc.), cannabinoid CB1antagonist (rimonabant etc.), FAAH inhibitor, sodium channel inhibitor,anti-ADHD drug (methylphenidate hydrochloride, methamphetaminehydrochloride etc.), therapeutic drug for alcoholism, therapeutic drugfor autism, therapeutic drug for chronic fatigue syndrome, therapeuticdrug for spasm, therapeutic drug for fibromyalgia syndrome, therapeuticdrug for headache, therapeutic drug for quitting smoking, therapeuticdrug for myasthenia gravis, therapeutic drug for cerebral infarction,therapeutic drug for mania, therapeutic drug for hypersomnia,therapeutic drug for pain, therapeutic drug for dysthymia, therapeuticdrug for autonomic ataxia, therapeutic drug for male and female sexualdysfunction, therapeutic drug for migraine, therapeutic drug forpathological gambler, therapeutic drug for restless legs syndrome,therapeutic drug for substance addiction, therapeutic drug foralcohol-related syndrome, therapeutic drug for irritable bowel syndrome,therapeutic drug for ALS (riluzole etc., neurotrophic factor etc.),therapeutic drug for lipid abnormality such as cholesterol-lowering drug(statin series (pravastatin sodium, atorvastatin, simvastatin,rosuvastatin etc.), fibrate (clofibrate etc.), squalene synthetaseinhibitor), therapeutic drug for abnormal behavior or suppressant ofdromomania due to dementia (sedatives, antianxiety drug etc.),antiobesity drug, therapeutic drug for diabetes, therapeutic agent fordiabetic complications, therapeutic drug for hypertension, therapeuticdrug for hypotension, diuretic, chemotherapeutic agent,immunotherapeutic agent, antithrombotic agent, anti-cancer agent and thelike.

Two or more kinds of the above-mentioned concomitant drug may be used ina mixture at an appropriate ratio.

When the compound of the present invention is applied to each of theabove-mentioned diseases, it can also be used in combination withbiologics (e.g., antibody drug, nucleic acid or nucleic acid derivative,aptamer drug, vaccine preparation), or can be combined with a genetherapy method and the like and applied as a combination therapy, or canalso be used in combination with a treatment in psychiatric fieldwithout using drugs.

Examples of the antibody and vaccine preparation include vaccinepreparation against angiotensin II, vaccine preparation against CETP,CETP antibody, antibody against TNFα antibody and other cytokines,amyloid β vaccine preparation, vaccine for type 1 diabetes (e.g.,DIAPEP-277 of Peptor), anti-HIV antibody and HIV vaccine preparation, aswell as antibodies or vaccine preparations against cytokines,renin-angiotensin type enzymes and products thereof, antibodies orvaccine preparations against enzymes or proteins involved in blood lipidmetabolism, antibodies or vaccines relating to enzymes and proteinsinvolved in blood coagulation or fibrinolysis system, antibodies orvaccine preparations against proteins involved in sugar metabolism andinsulin resistance, and the like. In addition, it can be used incombination with biologics relating to growth factors such as GH, IGFand the like.

Examples of the gene therapy method include a treatment method usinggene relating to cytokine, renin-angiotensin type enzyme and productthereof, G protein, G protein conjugated receptor and phosphorylatingenzyme thereof, a treatment method using a DNA decoy such as NFκB decoyand the like, a treatment method using antisense, a treatment methodusing a gene relating to a enzyme or protein involved in blood lipidmetabolism (e.g., a gene relating to metabolism, excretion andabsorption of cholesterol or triglyceride or HDL-cholesterol or bloodphospholipid), a treatment method using a gene relating to a enzyme orprotein involved in angiogenesis therapy for peripheral vascularobstruction and the like (e.g., growth factors such as HGF, VEGF etc.),a treatment method using a gene relating to a protein involved inglucose metabolism and insulin resistance, antisense against cytokinessuch as TNF etc., and the like.

Examples of the treatment method in the psychiatric field without usingdrug include modified electroconvulsive therapy, deep brain stimulationtherapy, repetitive transcranial magnetic stimulation therapy,psychotherapy including cognitive behavioral therapy and the like.

It can also be used in combination with various organ regenerationmethods such as cardiac regeneration, renal regeneration, pancreaticregeneration, revascularization and the like, cell transplantationtherapy utilizing bone marrow cells (bone marrow-derived mononuclearcell, myelogenic stem cell), or artificial organ utilizing tissueengineering (e.g., artificial blood vessel, cardiomyocyte sheet).

The compound of the present invention can be administered orally,parenterally (e.g., intramuscular, intraperitoneal, intravenous,intraarterial, intraventricular, intracisternal injection or infusion;subcutaneous injection; or implant), and by topical route such asinhalation spray, intratracheal, nasal, vaginal, rectal, sublingual,subdermal, transdermal and ocular instillation administration, in asuitable unit dosage form containing a pharmaceutically acceptableconventional nontoxic carrier, adjuvant and vehicle suitable for eachadministration route. In addition to the treatment of warm-bloodedanimals such as mouse, rat, horse, bovine, sheep, dog, cat, monkey andthe like, the compound of the present invention is effective for use inhuman.

A pharmaceutical composition for the administration of the compound ofthe present invention may conveniently be given in a unit dosage formand may be prepared by any of the methods well known in thepharmaceutical field. All methods include a step of mixing the activeingredient and one or more carriers constituting the auxiliarycomponents. Generally, a pharmaceutical composition is prepared byuniformly and completely admixing the active ingredient with liquidcarrier or finely-divided solid carrier or both, and then molding theproduct into a desirable dosage form as necessary. In a pharmaceuticalcomposition, the active compound of interest is included in an amountsufficient to produce a desired effect on the process or condition of adisease. As used herein, the term “composition” is intended to encompassa product comprising specified amounts of specified ingredients and allproducts obtained directly or indirectly from the combination of thespecified amounts of the specified ingredients.

A pharmaceutical composition for oral use may be prepared according toany method known in the this field relating to the manufacture ofpharmaceutical compositions, and such composition may contain one ormore agents selected from the group consisting of sweetener, flavor,colorant and preservative to provide a preparation havingpharmaceutically high quality and good taste. A tablet contains anactive ingredient in admixture with a pharmaceutically acceptablenon-toxic excipient suitable for the manufacture of tablets. Theseexcipients may be, for example, inert diluents such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate, sodiumphosphate and the like; granulating agent and disintegrant such ascornstarch, alginic acid and the like; binder such as starch, gelatin,acacia and the like; and lubricant such as magnesium stearate, stearicacid, talc and the like. Tablets may not be coated or coated by a knowntechnique for delaying disintegration and absorption in thegastrointestinal tract, whereby a sustained action is provided over alonger period of time. A composition for oral use may also be providedas a hard gelatin capsule wherein the active ingredient is mixed with aninert solid diluent such as calcium carbonate, calcium phosphate andkaolin, or as a soft gelatin capsule wherein the active ingredient ismixed with water or an oil medium, such as peanut oil, liquid paraffinand olive oil. An aqueous suspension contains an active material inadmixture with excipients suitable for the manufacture of an aqueoussuspension. An oily suspension may be formulated by suspending theactive ingredient in a suitable oil. An oil-in-water emulsion may alsobe adopted. Dispersible powders and granules suitable for thepreparation of an aqueous suspension by the addition of water provide anactive ingredient in admixture with a dispersing or wetting agent, asuspending agent, and one or more preservatives. The pharmaceuticalcomposition of the present compound may be in the form of a sterileinjectable aqueous or oily suspension. The compound of the invention mayalso be administered in the form of a suppository for rectaladministration. For topical use, cream, ointment, jelly, solution,suspension and the like containing the compound of the present inventionmay be employed. The compound of the present invention may also beformulated for the administration by inhalation. The compound of thepresent invention may also be administered by a transdermal patchaccording to a method known in this field.

While various production methods of the compound (I) of the presentinvention or a salt thereof (hereinafter to be simply referred to ascompound (I)) are considered, a representative example thereof is shownin the following scheme 1. In the explanation of the followingproduction method, a compound and a reaction product thereof to be thestarting materials may form a salt which does not adversely influencethe reaction.

Compound (I) is produced, for example, by the method shown in thefollowing scheme 1.

wherein R⁵ is a carbonyl group or a sulfonyl group substituted by R³,and other symbols are as defined above.

As compound (II) to be a starting material, for example, a commerciallyavailable compound or a compound known per se or a compound produced bya method analogous to the production method thereof can be used (e.g.,Organic Letters 2008, V10(13), 2701-2704) and the like).

Step 1 can be performed by a method known per se or a method analogousthereto. For example, alkylation reaction (e.g., S. R. Sandler and W.Karo, Organic Functional Group Preparations I, 2^(nd) ed., AcademicPress, 1983, Chapter 13) and the like) and the like can be used.

For step 2, for example, a method known per se (e.g., Journal of OrganicChemistry, 77(16), 6908-6916; 2012 and the like) and the like can beused.

Step 3 shows the production of compound (V) by reaction of compound (IV)with sulfonyl chloride, acyl chloride or isocyanate in the presence of abase.

As the base, organic bases (e.g., triethylamine, pyridine,diethylisopropylamine, sodium methoxide, sodium ethoxide and the like),inorganic bases (e.g., sodium hydroxide, potassium hydroxide, sodiumcarbonate, potassium carbonate, sodium hydrogen carbonate, potassiumhydrogen carbonate, cesium carbonate, sodium hydride, metal sodium andthe like) and the like are used. The amount of the base to be used isgenerally 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound(IV). As the kind of the base, an organic base is preferable, andtriethylamine, pyridine, diethylisopropylamine and the like,particularly pyridine, are preferable.

This reaction can be advantageously performed in a solvent. As thesolvent, hydrocarbons (e.g., pentane, hexane, cyclohexane, benzene,toluene and the like), ethers (e.g., diethyl ether, tetrahydrofuran,dioxane and the like), amides (e.g., N,N-dimethylformamide,hexamethylphosphoric acid triamide and the like), halogenatedhydrocarbons (e.g., dichloromethane, chloroform and the like),sulfoxides (e.g., dimethyl sulfoxide and the like), ureas (e.g.,1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H)-pyrimidine) and the like areused. When the aforementioned organic base is a liquid (e.g.,triethylamine, pyridine, diethylisopropylamine and the like), it canalso be used as a solvent. These solvents may be used alone or two ormore kinds thereof may be mixed at a suitable ratio and used. The amountof the solvent to be used is generally 1 to 100 ml, preferably 5 to 20ml, per 1 g of compound (IV). The reaction temperature is generally −20°C. to the boiling point of the solvent to be used for the reaction,preferably 0° C. to 60° C. While the reaction time varies depending onthe kind and amount of the base to be used and the like, it is 10 min to3 days, preferably 1 hr to 24 hr.

Step 4 can be performed according to, for example, a method known per se(e.g., Organic Letters 2011, V13(10), 2564-2567) and the like).

Step 5 can be performed according to, for example, a method known per se(e.g., WO 2011119541 A1 and the like).

Step 6 can be performed according to a method known per se (e.g., S. R.Sandler and W. Karo, Organic Functional Group Preparations II, 2^(nd)ed., Academic Press, 1989, Chapter 6) and the like).

In the thus-obtained compound (VII), an intramolecular functional groupcan also be converted to an object functional group by a combination ofchemical reactions known per se. Examples of the chemical reactioninclude oxidation reaction, reduction reaction, alkylation reaction,acylation reaction, ureation reaction, hydrolysis reaction, aminationreaction, esterification reaction, aryl coupling reaction, deprotectionreaction and the like.

In the above-mentioned production method, when a starting compound hasan amino group, a carboxyl group, a hydroxy group, a carbonyl group or amercapto group as a substituent, a protecting group generally used inthe peptide chemistry may be introduced into these groups, and theobject compound can be obtained by removing the protecting group asnecessary after the reaction.

Examples of the amino-protecting group include formyl group, C₁₋₆alkyl-carbonyl group, C₁₋₆ alkoxy-carbonyl group, benzoyl group, C₇₋₁₀aralkyl-carbonyl group (e.g., benzylcarbonyl), C₇₋₁₄ aralkyloxy-carbonylgroup (e.g., benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), tritylgroup, phthaloyl group, N,N-dimethylaminomethylene group, substitutedsilyl group (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl,tert-butyldimethylsilyl, tert-butyldiethylsilyl), C₂₋₆ alkenyl group(e.g., 1-allyl) and the like. These groups may be substituted by 1 to 3substituents selected from a halogen atom, a C₁₋₆ alkoxy group and anitro group.

Examples of the carboxyl-protecting group include C₁₋₆ alkyl group,C₇₋₁₀ aralkyl group (e.g., benzyl), phenyl group, trityl group,substituted silyl group (e.g., trimethylsilyl, triethylsilyl,dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl),C₂₋₆ alkenyl group (e.g., 1-allyl) and the like. These groups may besubstituted by 1 to 3 substituents selected from a halogen atom, a C₁₋₆alkoxy group and a nitro group.

Examples of the hydroxy-protecting group include C₁₋₆ alkyl group,phenyl group, trityl group, C₇₋₁₀ aralkyl group (e.g., benzyl), formylgroup, C₁₋₆ alkyl-carbonyl group, benzoyl group, a C₇₋₁₀aralkyl-carbonyl group (e.g., benzylcarbonyl), 2-tetrahydropyranylgroup, 2-tetrahydrofuranyl group, substituted silyl group (e.g.,trimethylsilyl, triethylsilyl, dimethylphenylsilyl,tert-butyldimethylsilyl, tert-butyldiethylsilyl), C₂₋₆ alkenyl group(e.g., 1-allyl) and the like. These groups may be substituted by 1 to 3substituents selected from a halogen atom, a C₁₋₆ alkyl group, a C₁₋₆alkoxy group and a nitro group.

Examples of the carbonyl-protecting group include cyclic acetal (e.g.,1,3-dioxane), non-cyclic acetal (e.g., di-C₁₋₆ alkylacetal) and thelike.

Examples of the mercapto-protecting group include C₁₋₆ alkyl group,phenyl group, trityl group, C₇₋₁₀ aralkyl group (e.g., benzyl), C₁₋₆alkyl-carbonyl group, benzoyl group, C₇₋₁₀ aralkyl-carbonyl group (e.g.,benzylcarbonyl), C₁₋₆ alkoxy-carbonyl group, C₆₋₁₄ aryloxy-carbonylgroup (e.g., phenyloxycarbonyl), C₇₋₁₄ aralkyloxy-carbonyl group (e.g.,benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), 2-tetrahydropyranylgroup, C₁₋₆ alkylamino-carbonyl group (e.g., methylaminocarbonyl,ethylaminocarbonyl) and the like. These groups may be substituted by 1to 3 substituents selected from a halogen atom, a C₁₋₆ alkyl group, aC₁₋₆ alkoxy group and a nitro group.

The above-mentioned protecting groups can be removed by a deprotectionreaction known per se.

Compound (I) obtained by the above-mentioned production method can beisolated and purified by a known means, such as solvent extraction,liquid conversion, phase transfer, crystallization, recrystallization,chromatography and the like.

When compound (I) contains optical isomer, stereoisomer, regio isomerand rotamer, these compounds are also included in compound (I), and eachcan be obtained as a single product by a synthesis method or aseparation method known per se. For example, when an optical isomerexists in compound (I), an optical isomer resolved from the compound isalso encompassed in compound (I).

Here, an optical isomer can be produced by a method known per se.

Compound (I) may be a crystal.

A crystal of compound (I) (hereinafter sometimes to be abbreviated asthe crystal of the present invention) can be produced by crystallizingcompound (I), by applying a crystallization method known per se.

The crystal of the present invention is superior in the physicochemicalproperties (e.g., melting point, solubility, stability) and biologicalproperties (e.g., pharmacokinetics (absorbability, distribution,metabolism, excretion), efficacy expression), and is extremely useful asa medicament.

EXAMPLE

The present invention is explained in detail in the following byreferring to Examples, Experimental Examples and Formulation Examples.However, the examples do not limit the present invention and the presentinvention can be modified within the scope of the present invention.

The “room temperature” in the following Examples is generally about 10°C. to about 35° C. The ratio for a mixed solvent is, unless otherwisespecified, a volume mixing ratio and % means wt % unless otherwisespecified.

The elution by column chromatography in the Examples was performed underthe observation by TLC (Thin Layer Chromatography) unless otherwisespecified. In the observation by TLC, 60 F₂₅₄ manufactured by Merck wasused as a TLC plate, the solvent used as an elution solvent in columnchromatography was used as an eluent, and UV detector was used for thedetection. In silica gel column chromatography, the indication of NHmeans use of aminopropylsilane-bonded silica gel and the indication ofDiol means use of 3-(2,3-dihydroxypropoxy) propylsilane-bonded silicagel. In preparative HPLC (high performance liquid chromatography), theindication of C18 means use of octadecyl-bonded silica gel. The ratio ofelution solvents is, unless otherwise specified, a volume mixing ratio.

In the following Examples, the following abbreviations are used.

THF: tetrahydrofuran, DMSO: dimethylsulfoxide, DME: 1,2-dimethoxyethane,IPE: isopropyl ether, PdCl₂(dppf):1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride, NMP:1-methyl-2-pyrrolidone, MPa: megapascal, psi: psi, CDCl₃:deuterochloroform, DMSO-d₆: deuterodimethyl sulfoxide

¹H NMR (proton nuclear magnetic resonance) was measured by Fouriertransform NMR. For the analysis of ¹H NMR, ACD/SpecManager (trade name)software and the like were used. Very mild peaks of protons of hydroxylgroup, amino group and the like are not described sometimes.

MS (mass spectrum) was measured by LC/MS (liquid chromatograph massspectrometer). As the ionization method, ESI (electrospray ionization)method, or APCI (atomospheric pressure chemical ionization) method wasused. The data indicates those found. While molecular ion peak isgenerally observed, a fragment ion is sometimes observed. In the case ofa salt, a molecular ion peak or fragment ion peak of free form isgenerally observed. Peaks by powder X-ray diffraction in the Examplesmean peaks measured at room temperature by using Ultima IV (RigakuCorporation, Japan) using Cu Kα radiation as a radiation source. Themeasurement conditions are as follows.

Electric pressure/Electric current: 40 kV/50 mA

Scan speed: 6 degrees/min

Scan range of 2 Theta: 2-35 degrees

The crystallinity by powder X-ray diffraction in the Examples wascalculated by the Hermans method.

Example 1N-(cis-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamideA) 3-bromo-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)pyridine

To a suspension of 60% sodium hydride (7.00 g) in THF (80 ml) was addedcis-4-isopropylcyclohexanol (19.91 g) at room temperature. The reactionmixture was stirred at room temperature overnight,3-bromo-2-(bromomethyl)pyridine (17.56 g) was added to the reactionmixture, and the mixture was stirred overnight at room temperature. Tothe mixture was added saturated aqueous ammonium chloride solution, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by NH silica gel chromatography (ethyl acetate/hexane) to givethe title compound (17.30 g).

MS, found: 312.2, 314.2.

B)N-(2-(((cis-4-isopropylcyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide

A mixture of 3-bromo-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)pyridine(3.0 g), methanesulfonamide (1.097 g),di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.408 g),tris(dibenzylideneacetone)dipalladium(0) (0.440 g), cesium carbonate(4.70 g) and THF (40 ml) was stirred with heating under microwaveradiation at 120° C. for 20 min. The reaction mixture was filteredthrough celite, and the filtrate was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel chromatography(ethyl acetate/hexane) to give the title compound (2.310 g).

MS, found: 327.3.

C)N-(cis-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

A mixture ofN-(2-(((cis-4-isopropylcyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide(2.285 g), platinum oxide (0.079 g), methanol (15 ml) and acetic acid(15 ml) was stirred overnight under a 0.6 MPa hydrogen atmosphere at 50°C. The mixture was filtrated, and the filtrate was neutralized withsaturated aqueous sodium hydrogen carbonate solution at 0° C. andextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby NH silica gel chromatography (ethyl acetate/hexane) to give the titlecompound (1.630 g).

¹H NMR (300 MHz, CDCl₃) δ 0.78-0.90 (6H, m), 0.96-1.15 (1H, m),1.20-1.48 (8H, m), 1.48-1.77 (9H, m), 1.79-1.90 (2H, m), 1.91-2.03 (1H,m), 2.67 (1H, td, J=11.8, 2.8 Hz), 2.86 (1H, ddd, J=7.9, 4.5, 1.9 Hz),3.04 (1H, dt, J=11.4, 2.4 Hz), 3.33 (1H, dd, J=9.4, 7.9 Hz), 3.46 (2H,dd, J=9.4, 4.5 Hz), 3.59 (1H, brs), 5.36 (1H, d, J=8.3 Hz).

Example 2(2R,3S)—N-ethyl-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)-3-((methylsulfonyl)amino)piperidine-1-carboxamide

To a solution of (2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinic acid (579mg) in ethanol (4 ml) was added a solution ofN-(cis-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(498 mg) in ethanol (4 ml) at room temperature, and the solution wasleft standing overnight. The resulting solid was collected byfiltration, and washed with acetonitrile to give a solid (270 mg). To asolution of the obtained solid (100 mg) and triethylamine (0.078 ml) inTHF (2 ml) was added ethylisocyanate (14.83 mg) at 0° C., and themixture was stirred at room temperature overnight. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel chromatography (ethylacetate/hexane) to give the title compound (54 mg).

¹H NMR (300 MHz, CDCl₃) δ 0.86 (6H, d, J=6.8 Hz), 1.20-1.25 (1H, m),1.34-1.53 (5H, m), 1.56-1.71 (8H, m), 1.71-1.81 (1H, m), 1.89 (2H, d,J=13.4 Hz), 2.82 (1H, td, J=12.7, 2.7 Hz), 3.00 (3H, s), 3.25 (2H, qd,J=7.2, 5.4 Hz), 3.48-3.61 (3H, m), 3.66-3.79 (1H, m), 3.87 (1H, dd,J=9.3, 7.8 Hz), 4.44-4.56 (1H, m), 4.66 (1H, t, J=4.9 Hz), 5.73 (1H, d,J=7.7 Hz).

Example 3N-((2R,3S)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamideA) 3-bromo-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyridine

To a solution of cis-4-phenylcyclohexanol (50.8 g) in THF (300 ml) wasadded 60% sodium hydride (17.29 g) at 0° C., and the mixture was stirredfor 30 min. To the reaction mixture was added3-bromo-2-(bromomethyl)pyridine (72.3 g), and the mixture was stirred atroom temperature overnight. Saturated aqueous ammonium chloride solutionwas added, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine, dried over anhydrous magnesium sulfateand the solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (84.43 g).

MS, found: 346.0, 348.0.

B)N-(2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide

To a mixture of 3-bromo-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyridine(38 g) in DME (450 ml) were addeddi-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (9.32 g),tris(dibenzylideneacetone)dipalladium(0) (10.05 g), cesium carbonate(53.6 g) and methanesulfonamide (12.53 g) at room temperature and thereaction mixture was stirred under a nitrogen atmosphere at 100° C. for5 hr. Water was added to the reaction mixture at room temperature, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine, dried over anhydrous magnesium sulfate and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give paleorange solid, which was recrystallized from ethyl acetate/hexane to givethe title compound (17.19 g).

MS, found: 361.2.

C)N-((2R,3S)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

A mixture ofN-(2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide(6.48 g), 5% rhodium/carbon (7.40 g), and ethanol/acetic acid (9:1)solution (222.22 ml) was stirred under a hydrogen atmosphere for 23.5hr. The reaction mixture was filtered through celite, and the solventwas evaporated under reduced pressure. The residue was diluted withethyl acetate, washed successively with saturated aqueous sodiumhydrogen carbonate solution, and saturated brine, dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.To a solution of the obtained residue (6.80 g) in ethyl acetate (48 ml)was added a solution of (+)-mandelic acid (2.82 g) in ethyl acetate (20ml) at 60° C., and the mixture was stirred at the same temperature for 1hr. Seed crystal was added to the reaction mixture at 50° C., and themixture was gradually cooled to room temperature and stirred at roomtemperature overnight. The salt was collected by filtration, and washedwith a mixed solvent of ethyl acetate/IPE (2:3). The solid wasrecrystallized from a mixed solvent of ethyl acetate/acetonitrile (1:1).The obtained crystal was dissolved in ethyl acetate-10% aqueouspotassium carbonate solution, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure to give the title compound (1.09 g).

¹H NMR (300 MHz, CDCl₃) δ 1.47-1.86 (10H, m), 1.92-2.08 (3H, m), 2.53(1H, tt, J=11.4, 3.7 Hz), 2.69 (1H, td, J=11.6, 2.8 Hz), 2.86-2.94 (1H,m), 2.98 (3H, s), 3.02-3.12 (1H, m), 3.32-3.42 (1H, m), 3.51 (1H, dd,J=9.3, 4.4 Hz), 3.57-3.68 (2H, m), 5.38 (1H, d, J=7.2 Hz), 7.13-7.37(5H, m).

Example 4N-((2R,3S)-1-acetyl-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

A reaction mixture ofN-((2R,3S)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(220 mg), pyridine (4 ml), and acetic anhydride (1 ml) was stirred atroom temperature overnight. The reaction mixture was concentrated underreduced pressure, and the residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (249mg).

¹H NMR (300 MHz, CDCl₃) δ 1.48-2.65 (15H, m), 2.94-3.16 (4H, m),3.43-5.20 (7H, m), 5.31-6.22 (1H, m), 7.13-7.36 (5H, m).

Example 5 Methyl(2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate

To a reaction mixture ofN-((2R,3S)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(58 mg), triethylamine (0.044 ml) in THF (3 ml) was added methylchloroformate (0.024 ml) at room temperature, and the mixture wasstirred overnight under a calcium chloride tube dry atmosphere. To thereaction mixture was added water, and the mixture was extracted withethyl acetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (64 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.48-1.58 (2H, m), 1.59-1.67 (2H, m),1.68-1.89 (6H, m), 2.01-2.12 (3H, m), 2.47-2.61 (1H, m), 2.73-2.88 (1H,m), 2.99 (3H, s), 3.53-3.63 (2H, m), 3.64-3.69 (1H, m), 3.70-3.77 (3H,m), 4.00-4.10 (1H, m), 4.48-4.73 (1H, m), 6.00 (1H, brs), 7.14-7.26 (3H,m), 7.27-7.35 (2H, m).

Example 5A Methyl(2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate

To a solution ofN-((2R,3S)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(1.09 g) in THF (25 ml) were added methyl chloroformate (337 mg) andtriethylamine (0.622 ml) at room temperature, and the mixture wasstirred over weekend. Saturated aqueous ammonium chloride solution wasadded, and the mixture was extracted with ethyl acetate. The extract waswashed with saturated brine, dried over anhydrous sodium sulfate and thesolvent was evaporated under reduced pressure. The residue was dissolvedin hot ethanol (3 ml), and the solution was stirred at room temperaturefor 10 min. After crystals started to precipitate, water (3 ml) wasadded to the solution and then stirred overnight. The crystals werecollected by filtration to give crystals of the title compound (1.023g).

X-ray powder diffraction patterns of the obtained crystals weregenerated using Ultima IV with Cu Kα radiation.

The obtained crystal showed a powder X-ray diffraction pattern havingcharacteristic peaks at the diffraction angle (2θ) of 8.8°, 11.0°,13.4°, 15.3°, 17.6°, 19.2°, 20.4° and 23.4°.

Example 6N-(cis-2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamideacetate A)3-bromo-2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)pyridine

A solution of cis-4-(3,5-difluorophenyl)cyclohexanol (1.91 g) in THF (40ml) was cooled to 0° C., 60% sodium hydride (0.720 g) was added, and themixture was stirred at room temperature under a calcium chloride tubedry atmosphere for 2 hr. To the reaction mixture was added3-bromo-2-(bromomethyl)pyridine (2.416 g), and the mixture was stirredat room temperature for 30 min, and at 70° C. for 3 hr. To the mixturewas added water at room temperature, and the mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography (ethyl acetate/hexane) to give the title compound(3.33 g).

MS, found: 382.0, 384.0.

B)N-(2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide

A mixture of3-bromo-2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)pyridine(3.3 g), methanesulfonamide (0.985 g),di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.440 g),tris(dibenzylideneacetone)dipalladium(0) (0.395 g), cesium carbonate(4.22 g) and DME (40 ml) was heated under reflux at 95° C. under anitrogen atmosphere for 6 hr. To the reaction mixture was added water atroom temperature, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel chromatography (ethylacetate/hexane) to give the title compound (3.20 g).

MS, found: 397.2.

C)N-(cis-2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamideacetate

A mixture ofN-(2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide(1.95 g), 5% rhodium/carbon (2.025 g), ethanol (45 ml) and acetic acid(5.0 ml) was stirred at room temperature under a hydrogen atmosphere for6 hr. The mixture was filtrated, toluene was added to the filtrate, andthe mixture was concentrated under reduced pressure. The residue waswashed with IPE to give the title compound (1.5045 g).

MS, found: 403.2.

Example 7N-((2R,3S)-2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

N-(cis-2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamideacetate (1.15 g) was dissolved in ethyl acetate and the mixture wasbasified with 1 mol/l aqueous sodium hydroxide solution. The organiclayer was washed with saturated brine, dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. From theresidue (0.976 g) was separated 295.5 mg by HPLC (column: CHIRALPAK AD(LF001), 50 mmID×500 mmL, manufactured by Daicel Corporation, mobilephase: hexane/2-propanol/diethylamine=700/300/1) and a fraction having ashorter retention time was obtained as the title compound (0.143 g).

¹H NMR (300 MHz, CDCl₃) δ 1.45-1.59 (3H, m), 1.60-1.77 (6H, m),1.81-1.89 (1H, m), 1.89-2.04 (2H, m), 2.52 (1H, tt, J=11.1, 4.0 Hz),2.64-2.76 (1H, m), 2.90 (1H, ddd, J=8.1, 4.4, 1.9 Hz), 2.94-3.01 (3H,m), 3.07 (1H, dt, J=11.5, 2.4 Hz), 3.30-3.42 (1H, m), 3.46-3.55 (1H, m),3.56-3.67 (2H, m), 3.71-3.79 (1H, m), 5.35 (1H, d, J=8.0 Hz), 6.61 (1H,tt, J=8.9, 2.3 Hz), 6.69-6.79 (2H, m).

Example 8N-((2R,3S)-1-acetyl-2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

To a solution ofN-((2R,3S)-2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(200 mg) and triethylamine (0.138 ml) in THF (5 ml) was added acetylchloride (0.068 ml) at room temperature, and the mixture was stirredunder a calcium chloride tube dry atmosphere for 30 min. To the mixturewas added water at room temperature, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel chromatography(ethyl acetate/hexane) to give the title compound (218 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.52 (1H, brs), 1.58-1.88 (7H, m), 1.97-2.25(6H, m), 2.44-2.66 (1H, m), 2.92-3.14 (4H, m), 3.39-3.75 (4.5H, m),3.84-4.08 (1H, m), 4.38 (0.5H, brs), 5.11 (1H, brs), 5.24-6.18 (1H, m),6.62 (1H, tt, J=9.0, 2.3 Hz), 6.76 (2H, d, J=6.8 Hz).

Example 9N-(cis-2-(((cis-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamideA) 8-(2,5-difluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene

To a mixed solution of (2,5-difluorophenyl)boronic acid (4.11 g),1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (5 g), sodiumcarbonate (7.35 g), and lithium chloride (0.037 g) in DME (60 ml)-water(15.00 ml) was added tetrakis(triphenylphosphine)palladium(0) (1.002 g)at room temperature. The mixture was heated under reflux at 100° C.under a nitrogen atmosphere overnight. To the mixture was added water atroom temperature, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel chromatography (ethyl acetate/hexane)to give the title compound (3.582 g).

MS, found: 253.0.

B) 8-(2,5-difluorophenyl)-1,4-dioxaspiro[4.5]decane

To a solution of 8-(2,5-difluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene(800 mg) in ethanol (15 ml) was added 10% palladium/carbon (337 mg) atroom temperature. The mixture was stirred at room temperature under ahydrogen atmosphere for 1 hr. The mixture was filtered, and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel chromatography (ethyl acetate/hexane) to give the titlecompound (754 mg).

MS, found: 255.0.

C) 4-(2,5-difluorophenyl)cyclohexanone

To a solution of 8-(2,5-difluorophenyl)-1,4-dioxaspiro[4.5]decane (4.15g) in acetone (30 ml) was added 2 mol/l hydrochloric acid (30 ml) atroom temperature. The mixture was stirred at 60° C. for 2 hr. Thereaction mixture was partitioned by adding ethyl acetate. The organiclayer was washed with saturated aqueous sodium hydrogen carbonatesolution and saturated brine, dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel chromatography (ethyl acetate/hexane) to give thetitle compound (3.32 g).

MS, found: 211.0.

D) cis-4-(2,5-difluorophenyl)cyclohexanol

To a solution of 4-(2,5-difluorophenyl)cyclohexanone (3.32 g) in THF(150 ml) was added lithium tri-(sec-butyl)borohydride 1 mol/l THFsolution (46.0 ml) at −78° C. The mixture was stirred at 0° C. for 3 hr.To the mixture was added dropwise 30% hydrogen peroxide water at 0° C.,and the mixture was stirred for 5 min. To the reaction mixture wereadded acetone (22 ml), water (52 ml), 30% hydrogen peroxide water (22ml) in this order, and the mixture was stirred for 5 min and extractedwith ethyl acetate. The organic layer was washed with water andsaturated brine, dried over anhydrous magnesium sulfate, and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel chromatography (ethyl acetate/hexane) to give the titlecompound (2.85 g).

¹H NMR (300 MHz, CDCl₃) δ 1.31 (1H, d, J=2.3 Hz), 1.64-1.99 (8H, m),2.75-2.98 (1H, m), 4.07-4.23 (1H, m), 6.74-7.06 (3H, m).

E) 3-bromo-2-(((cis-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)pyridine

A solution of cis-4-(2,5-difluorophenyl)cyclohexanol (2.85 g) in THF (60ml) was cooled to 0° C., 60% sodium hydride (1.074 g) was added, and themixture was stirred under a calcium chloride tube dry atmosphere at roomtemperature for 2 hr. To the reaction mixture was added3-bromo-2-(chloromethyl)pyridine (3.60 g), and the mixture was stirredat room temperature for 30 min and at 70° C. for 3 hr. Water was addedto the mixture at room temperature, and the mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography (ethyl acetate/hexane) to give the title compound(4.33 g).

MS, found: 382.0, 383.9.

F) N-(2-(((cis-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide

To a mixed solution of3-bromo-2-(((cis-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)pyridine(4.33 g), methanesulfonamide (1.293 g),di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.962 g),and cesium carbonate (5.54 g) in DME (65 ml) was addedtris(dibenzylideneacetone)dipalladium(0) (1.037 g) at room temperature.The mixture was heated under reflux at 100° C. under a nitrogenatmosphere for 6 hr. Water was added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel chromatography (ethyl acetate/hexane) to give the titlecompound (3.95 g).

MS, found: 397.1.

G)N-(cis-2-(((cis-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

To a mixed solution ofN-(2-(((cis-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide(3.76 g) in ethanol (99 ml) and acetic acid (11.00 ml) was added 5%rhodium/carbon (3.90 g) at room temperature. The mixture was stirred atroom temperature under a hydrogen atmosphere for 11 hr. The mixedsolution was filtered, and the solvent was evaporated under reducedpressure. After washing with IPE-methanol, the residue was suspended insaturated aqueous sodium hydrogen carbonate solution, and the suspensionwas extracted with ethyl acetate. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure to give the title compound (2.015 g).

¹H NMR (300 MHz, CDCl₃) δ 1.44-1.65 (7H, m), 1.69-1.82 (3H, m), 2.02(3H, d, J=13.3 Hz), 2.59-2.75 (1H, m), 2.80-2.94 (2H, m), 2.96-3.00 (3H,m), 3.08 (1H, dt, J=11.5, 2.4 Hz), 3.31-3.42 (1H, m), 3.51 (1H, dd,J=9.3, 4.4 Hz), 3.62 (2H, d, J=2.7 Hz), 5.37 (1H, d, J=6.1 Hz),6.73-6.87 (1H, m), 6.89-7.02 (2H, m).

Example 10N-((2R,3S)-2-(((cis-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

N-(cis-2-(((cis-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamidewas separated by HPLC (column: CHIRALPAK AD(LF001), 50 mmID×500 mmL,manufactured by Daicel Corporation, mobile phase:hexane/2-propanol/diethylamine=700/300/1) and a fraction having ashorter retention time was obtained as the title compound (0.718 g).

¹H NMR (300 MHz, CDCl₃) δ 1.48-1.65 (6H, m), 1.70-1.83 (4H, m),1.93-2.12 (3H, m), 2.70 (1H, td, J=11.6, 2.8 Hz), 2.80-2.95 (2H, m),2.98 (3H, s), 3.09 (1H, dt, J=11.5, 2.2 Hz), 3.30-3.43 (1H, m),3.48-3.55 (1H, m), 3.59-3.70 (2H, m), 5.30-5.60 (1H, m), 6.76-6.87 (1H,m) 6.88-7.04 (2H, m).

Example 11 methyl(2R,3S)-2-(((cis-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate

To a solution ofN-((2R,3S)-2-(((cis-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(300 mg) and triethylamine (0.207 ml) in THF (5 ml) was added methylchloroformate (0.115 ml) at room temperature, and the mixture wasstirred for 1 hr. Water was added to the mixture at room temperature,and the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel chromatography (ethyl acetate/hexane) to give thetitle compound (329 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.50-1.56 (1H, m), 1.59-1.91 (8H, m), 2.03(1H, brs), 2.08 (2H, brs), 2.70-2.95 (2H, m), 3.01 (3H, s), 3.53-3.71(3H, m), 3.73 (3H, s), 3.84-4.08 (2H, m), 4.63 (1H, brs), 5.96 (1H,brs), 6.77-6.88 (1H, m), 6.89-7.06 (2H, m).

Example 12N-(cis-2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamideA) cis-4-(2,6-difluorophenyl)cyclohexanol

To a solution of 4-(2,6-difluorophenyl)cyclohexanone (2.71 g) in THF(120 ml) was added lithium tri(sec-butyl)borohydride 1 mol/l THFsolution (37.0 ml) at −78° C. The mixture was warmed to 0° C. over 3 hr.To the mixture were added dropwise acetone, water and 30% hydrogenperoxide water at 0° C. and the mixture was stirred for 5 min andextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel chromatography (ethyl acetate/hexane) to give the titlecompound (2.69 g).

¹H NMR (300 MHz, CDCl₃) δ 1.40 (1H, d, J=4.5 Hz), 1.56-1.74 (4H, m),1.84-2.01 (2H, m), 2.25 (2H, d, J=14.0 Hz), 3.02 (1H, tt, J=12.6, 3.3Hz), 4.13 (1H, brs), 6.73-6.92 (2H, m), 7.01-7.20 (1H, m).

B) 3-bromo-2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)methyl)pyridine

A solution of cis-4-(2,6-difluorophenyl)cyclohexanol (2.69 g) in THF (60ml) was cooled to 0° C., 60% sodium hydride (1.014 g) was added, and themixture was stirred under a calcium chloride tube dry atmosphere for 2hr. To the reaction mixture was added 3-bromo-2-(chloromethyl)pyridine(3.40 g), and the mixture was stirred at room temperature for 30 min,and at 70° C. overnight. Water was added to the mixture at roomtemperature, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel chromatography(ethyl acetate/hexane) to give the title compound (3.96 g).

MS, found: 382.0, 384.0.

C) N-(2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide

A mixture of3-bromo-2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)methyl)pyridine(3.96 g), methanesulfonamide (1.183 g),di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.880 g),tris(dibenzylideneacetone)dipalladium(0) (0.949 g), cesium carbonate(5.06 g) and DME (60 ml) was heated under reflux at 100° C. under anitrogen atmosphere for 6 hr. Water was added to the reaction mixture atroom temperature, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel chromatography (ethylacetate/hexane) to give the title compound (3.76 g).

MS, found: 397.1.

D)N-(cis-2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

A mixture ofN-(2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide(3.76 g), 5% rhodium/carbon (3.90 g), ethanol (99 ml) and acetic acid(11.0 ml) was stirred at room temperature under a hydrogen atmospherefor 9 hr. The mixture was filtered, and the solvent was evaporated underreduced pressure. The residue was washed with IPE. The obtained solidwas dissolved in saturated aqueous sodium hydrogen carbonate solutionand then neutralized, and extracted with ethyl acetate. The organiclayer was dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by NH silicagel chromatography (ethyl acetate/hexane) to give the title compound(1.84 g).

¹H NMR (300 MHz, CDCl₃) δ 1.40-1.80 (8H, m), 1.92-2.22 (5H, m), 2.71(1H, td, J=11.7, 2.6 Hz), 2.89-3.13 (6H, m), 3.35-3.44 (1H, m),3.45-3.53 (1H, m), 3.63 (2H, brs), 5.40 (1H, brs), 6.69-6.94 (2H, m),7.01-7.22 (1H, m).

Example 13N-((2R,3S)-2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

N-(cis-2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(1800 mg) was separated by HPLC (column: CHIRALPAK AD(LF001), 50mmID×500 mmL, manufactured by Daicel Corporation, mobile phase:hexane/2-propanol/diethylamine=800/200/1) and a fraction having ashorter retention time was obtained as the title compound (593.2 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.51 (4H, dd, J=9.8, 4.2 Hz), 1.65-1.82 (4H,m), 1.93-2.28 (5H, m), 2.71 (1H, td, J=11.6, 2.8 Hz), 2.85-3.13 (6H, m),3.31-3.44 (1H, m), 3.44-3.51 (1H, m), 3.63 (2H, brs), 5.40 (1H, brs),6.70-6.94 (2H, m), 7.10 (1H, tt, J=8.3, 6.4 Hz).

Example 14N-((2R,3S)-1-acetyl-2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

To a solution ofN-((2R,3S)-2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(51.9 mg) in pyridine (2.0 ml) was added acetic anhydride (0.036 ml) atroom temperature, and the mixture was stirred under a calcium chloridetube dry atmosphere for 30 min. Toluene was added to the mixture, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel chromatography (ethyl acetate/hexane) to give thetitle compound (53.1 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.56-1.65 (3H, m), 1.68-2.24 (11H, m),2.60-3.35 (5H, m), 3.44-3.81 (4H, m), 3.82-3.95 (1H, m), 4.26-4.66 (1H,m), 4.98-5.47 (1H, m), 5.72 (1H, d, J=8.3 Hz), 6.82 (2H, t, J=8.5 Hz),7.11 (1H, tt, J=8.3, 6.3 Hz).

Example 15N-(2-(((cis-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamideA) 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene

To a mixed solution of (3-fluorophenyl)boronic acid (7.28 g),1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (10 g),sodium carbonate (7.35 g), and lithium chloride (0.147 g) in DME (150ml)-water (30.0 ml) was added tetrakis(triphenylphosphine)palladium(0)(2.005 g) at room temperature. The mixture was heated under reflux at100° C. under a nitrogen atmosphere for 3 hr. Water was added to themixture at room temperature, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel chromatography (ethylacetate/hexane) to give the title compound (5.13 g).

MS, found: 235.0.

B) 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]decane

To a solution of 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (2.40g) in ethanol (30 ml) was added 10% palladium/carbon (1.090 g) at roomtemperature. The mixture was stirred at room temperature under ahydrogen atmosphere for 2 hr. The mixed solution was filtered, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel chromatography (ethyl acetate/hexane) to give the titlecompound (1.900 g).

MS, found: 237.0.

C) 4-(3-fluorophenyl)cyclohexanone

To a solution of 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (3.96g) in acetone (30 ml) was added 6 mol/l hydrochloric acid (3 ml) at roomtemperature. The mixture was stirred at room temperature overnight. Thesolvent was evaporated under reduced pressure. To the mixture was addedsaturated brine, and the mixture was extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel chromatography (ethyl acetate/hexane) to give the titlecompound (3.01 g).

MS, found: 193.1.

D) cis-4-(3-fluorophenyl)cyclohexanol

To 4-(3-fluorophenyl)cyclohexanone (380 mg) in THF (15 ml) was addedlithium tri(sec-butyl)borohydride 1 mol/l THF solution (3.95 ml) at −78°C. The mixture was stirred at 0° C. for 2 hr. To the reaction mixturewas added saturated aqueous ammonium chloride solution, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel chromatography (ethyl acetate/hexane) to give the titlecompound (325 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.31 (1H, s), 1.60-1.76 (4H, m), 1.77-1.98(4H, m), 2.45-2.62 (1H, m), 4.10-4.18 (1H, m), 6.82-6.97 (2H, m), 7.01(1H, d, J=7.6 Hz), 7.18-7.26 (1H, m).

E) 3-bromo-2-(((cis-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)pyridine

A solution of cis-4-(3-fluorophenyl)cyclohexanol (1.0 g) in THF (20 ml)was cooled to 0° C., 60% sodium hydride (0.412 g) was added, and themixture was stirred under a calcium chloride tube dry atmosphere for 1hr. To the reaction mixture was added 3-bromo-2-(chloromethyl)pyridine(1.382 g), and the mixture was stirred at room temperature for 2 hr, andat 70° C. for 2.5 hr. To the mixture was added saturated aqueousammonium chloride solution at room temperature, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel chromatography (ethyl acetate/hexane) to give the titlecompound (1.580 g).

MS, found: 363.9, 365.9.

F)N-(2-(((cis-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide

To a solution of3-bromo-2-(((cis-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)pyridine (1.15g), methanesulfonamide (0.601 g),di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.134 g),and cesium carbonate (2.057 g) in DME (20 ml) was addedtris(dibenzylideneacetone)dipalladium(0) (0.289 g) at room temperature.The mixture was stirred under microwave radiation at 120° C. for 2 hr.The reaction mixture was filtered through celite, and the filtrate waswashed with saturated brine, dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel chromatography (ethyl acetate/hexane) to give thetitle compound (1.100 g).

MS, found: 379.0.

G)N-((2R,3S)-2-(((cis-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

To a mixed solution of a solution ofN-(2-(((cis-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide(2.82 g) in ethanol (40 ml) and acetic acid (2.105 ml) was added 5%rhodium/carbon (3.07 g) at room temperature. The mixture was stirred atroom temperature under a hydrogen atmosphere overnight. The mixedsolution was filtered, and the solvent was evaporated under reducedpressure. The residue was dissolved in saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, and the solvent wasevaporated under reduced pressure. The residue was separated by HPLC(column: CHIRALPAK AD(AF003), 50 mmID×500 mmL, manufactured by DaicelCorporation, mobile phase: hexane/2-propanol/diethylamine=650/350/1) anda fraction having a shorter retention time was obtained as the titlecompound (1.040 g).

¹H NMR (300 MHz, CDCl₃) δ 1.50-1.76 (10H, m), 1.92-2.07 (3H, m), 2.54(1H, tt, J=11.4, 4.0 Hz), 2.69 (1H, td, J=11.7, 2.7 Hz), 2.90 (1H, ddd,J=8.0, 4.3, 2.1 Hz), 2.97 (3H, s), 3.07 (1H, dt, J=11.5, 2.4 Hz),3.29-3.42 (1H, m), 3.49-3.54 (1H, m), 3.49-3.54 (1H, m), 3.56-3.66 (2H,m), 5.38 (1H, d, J=7.6 Hz), 6.82-6.95 (2H, m), 6.99 (1H, d, J=7.6 Hz),7.18-7.26 (1H, m).

Example 16N-((2R,3S)-1-(cyclopropylcarbonyl)-2-(((cis-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

To a solution ofN-((2R,3S)-2-(((cis-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(60 mg), triethylamine (0.043 ml) in THF (4 ml) was addedcyclopropanecarbonyl chloride (0.028 ml) at room temperature, and themixture was stirred for 1 hr. Water was added to the mixture at roomtemperature, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel chromatography (ethylacetate/hexane) to give the title compound (59.3 mg).

¹H NMR (300 MHz, CDCl₃) δ 0.80 (2H, dd, J=7.8, 3.6 Hz), 0.92-1.05 (2H,m), 1.52 (1H, d, J=2.3 Hz), 1.59-2.25 (12H, m), 2.54 (1H, dt, J=15.0,7.7 Hz), 2.92-3.20 (4H, m), 3.43-3.73 (3H, m), 4.00 (1H, t, J=9.1 Hz),4.50 (1H, brs), 4.65-5.23 (1H, m), 5.42-6.37 (1H, m), 6.81-6.97 (2H, m),7.01 (1H, d, J=7.6 Hz), 7.19-7.26 (1H, m).

Example 17N-(cis-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamideA) 8-(2,3-difluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene

To a solution of 1,4-dioxaspiro[4.5]dec-7-en-8-yltrifluoromethanesulfonate (20.0 g) in DME/water (4:1) (250 ml) wereadded 2,3-difluorophenylboronic acid (16.45 g), lithium chloride (1.0g), and sodium carbonate (29.8 g).Tetrakis(triphenylphosphine)palladium(0) (6.42 g) was added, and thereaction mixture was stirred with heating under reflux for 16 hr. Thereaction mixture was diluted with ethyl acetate and filtered throughcelite. The filtrate was successively washed with water and saturatedbrine, dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (11.0 g).

¹H NMR (400 MHz, DMSO-d₆) δ 1.80 (2H, t, J=6.4 Hz), 2.38 (2H, s), 2.50(2H, brs), 3.93 (4H, s), 5.88 (1H, s), 7.12-7.19 (1H, m), 7.25-7.34 (1H,m), 7.41 (1H, t, J=7.6 Hz).

B) 8-(2,3-difluorophenyl)-1,4-dioxaspiro[4.5]decane

A solution of 8-(2,3-difluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (10.0g) in ethanol (500 ml) was deaerated with an argon stream for 15 min,and 10% palladium/carbon (1 g) was added. The reaction mixture wasstirred under normal pressure hydrogen atmosphere at room temperaturefor 2 hr. The reaction mixture was filtered through celite, and theresidue was washed with ethanol. The filtrate was concentrated underreduced pressure to give the title compound (8.0 g).

¹H NMR (400 MHz, DMSO-d₆) δ 1.61-1.78 (8H, m), 2.90-2.93 (1H, m), 3.89(4H, s), 7.11-7.18 (1H, m), 7.21 (1H, m), 7.40 (1H, t, J=8.1 Hz).

C) 4-(2,3-difluorophenyl)cyclohexanone

To a solution of 8-(2,3-difluorophenyl)-1,4-dioxaspiro[4.5]decane (8.0g) in THF/water (1:1) (100 ml) was added concentrated sulfuric acid (6.4ml) at 0° C., and the mixture was stirred at room temperature for 16 hr.To the reaction mixture was added aqueous sodium carbonate solution at0° C., and the mixture was extracted with ethyl acetate. The extract wassuccessively washed with water and saturated brine, dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (6.0 g).

¹H NMR (400 MHz, DMSO-d₆) δ 1.87-1.98 (2H, m), 2.03-2.07 (2H, m),2.26-2.29 (2H, m), 2.59-2.67 (2H, m), 3.35-3.44 (1H, m), 7.14-7.22 (1H,m), 7.25-7.31 (1H, m), 7.41 (1H, t, J=7.7 Hz).

D) cis-4-(2,3-difluorophenyl)cyclohexanol

To a solution of 4-(2,3-difluorophenyl)cyclohexanone (3.0 g) in THF (20ml) was added lithium tri(sec-butyl)borohydride 1 mol/l THF solution(21.43 ml) at −78° C., and the mixture was stirred at the sametemperature for 30 min. The reaction mixture was gradually warmed to 0°C., and stirred at 0° C. for 2 hr. To the reaction mixture weresuccessively added dropwise at 0° C. water and 1 mol/l aqueous sodiumhydroxide solution, and the mixture was extracted with ethyl acetate.The extract was successively washed with water and saturated brine,dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (1.3g).

¹H NMR (400 MHz, DMSO-d₆) δ 1.49-1.59 (4H, m), 1.73-1.77 (2H, m),1.82-1.91 (2H, m), 2.80-2.86 (1H, m), 3.90-3.91 (1H, m), 4.38-4.39 (1H,m), 7.12-7.26 (3H, m).

E) 3-bromo-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)pyridine

To a solution of cis-4-(2,3-difluorophenyl)cyclohexanol (1.3 g) in THF(5 ml) was added 60% sodium hydride (610 mg) at 0° C., and the mixturewas stirred with heating under reflux for 2 hr. To the reaction mixturewas slowly added a solution of 3-bromo-2-(bromomethyl)pyridine (2.31 g)in THF (5 ml) at room temperature, and the reaction mixture was stirredwith heating under reflux for 4 hr. To the reaction mixture was addedwater, and the mixture was neutralized with 1 mol/l hydrochloric acidand extracted with ethyl acetate. The extract was successively washedwith water and saturated brine, dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (810 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.52-1.60 (4H, m), 1.75-1.85 (2H, m),2.00-2.03 (2H, m), 2.86-2.92 (1H, m), 3.78 (1H, s), 4.60 (2H, s),7.10-7.20 (2H, m), 7.22-7.26 (1H, m), 7.32-7.35 (1H, m), 8.10 (1H, dd,J=8.1, 1.1 Hz), 8.55 (1H, dd, J=4.5, 1.2 Hz).

F)N-(2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide

To a solution of3-bromo-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)pyridine(800 mg) in dioxane (5 ml) were added methanesulfonamide (345 mg) andcesium carbonate (1.02 g). The reaction mixture was aerated with anargon stream for 20 min,di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (178 mg) andtris(dibenzylideneacetone)dipalladium(0) (192 mg) were added, and themixture was sealed and stirred under an argon atmosphere at 120° C. for4 hr. The reaction mixture was filtered through celite, and the residuewas washed with ethyl acetate. The filtrate was successively washed withwater and saturated brine, dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (620 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.53-1.61 (4H, m), 1.70-1.76 (2H, m),1.99-2.05 (2H, m), 2.87-2.93 (1H, m), 3.10 (3H, s), 3.79 (1H, brs), 4.75(2H, s), 7.10-7.15 (2H, m), 7.22-7.24 (1H, m), 7.37-7.41 (1H, m), 7.79(1H, d, J=8.0 Hz), 8.37-8.38 (1H, m), 9.11 (1H, brs).

G)N-(cis-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

To a solution ofN-(2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide(600 mg) in methanol/acetic acid (10:1) (66 ml) was added platinum oxide(60 mg). The reaction mixture was stirred under a 40 psi hydrogenatmosphere for 16 hr at room temperature. The reaction mixture wasfiltered through celite, and the residue was washed with methanol. Thefiltrate was concentrated under reduced pressure, and the residue wasdissolved in ethyl acetate and the mixture was successively washed withsaturated aqueous sodium hydrogen carbonate solution and saturatedbrine, dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by NH silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (400 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 1.35-1.38 (1H, m), 1.50-1.56 (5H, m),1.68-1.98 (7H, m), 2.54-2.57 (1H, m), 2.84-2.90 (3H, m), 2.93 (3H, s),3.36-3.40 (2H, m), 3.51 (1H, brs), 3.59 (1H, brs), 6.72 (1H, brs),7.11-7.18 (2H, m), 7.19-7.26 (1H, m).

Example 18N-((2R,3S)-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

N-(cis-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(3.5 g) was separated by HPLC (column: CHIRALPAK AD(LF001), 50 mmID×500mmL, manufactured by Daicel Corporation, mobile phase:hexane/2-propanol/diethylamine=700/100/1), and a fraction having ashorter retention time was obtained as the title compound (1.57 g)

¹H NMR (300 MHz, CDCl₃) δ 1.48-1.64 (6H, m), 1.70-1.86 (3H, m), 2.69(1H, td, J=11.7, 2.7 Hz), 2.85-1.96 (2H, m), 2.97-3.00 (3H, m), 3.07(1H, dt, J=11.5, 2.4 Hz), 3.28-3.56 (3H, m), 3.63 (2H, d, J=2.7 Hz),5.38 (1H, dt, J=8.3 Hz), 6.90-7.06 (3H, m).

Example 19N-((2R,3S)-1-acetyl-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

To a solution ofN-((2R,3S)-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(300 mg) in THF (15 ml) were added acetyl chloride (0.079 ml) andtriethylamine (0.208 ml) at room temperature, and the mixture wasstirred at the same temperature for 4 hr. To the reaction mixture wasadded saturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The extract was successively washed withsaturated aqueous ammonium chloride solution and saturated brine, driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (315mg).

¹H NMR (300 MHz, CDCl₃) δ 1.59-1.90 (8H, m), 1.95-2.24 (6H, m),2.79-4.43 (10H, m), 4.48-6.25 (2H, m), 6.87-7.16 (3H, m).

Example 20 methyl(2R,3S)-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)-3-((methylsulfonyl)amino)piperidine-1-carboxylate

To a solution ofN-((2R,3S)-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(50 mg) in THF (5 ml) were added methyl chloroformate (18 mg) andtriethylamine (38 mg) at room temperature, and the mixture was stirredat the same temperature overnight. To the reaction mixture was addedsaturated aqueous ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (52 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.51-2.12 (12H, m), 2.74-2.86 (1H, m),2.87-2.98 (1H, m), 3.00 (3H, s), 3.54-3.65 (2H, m), 3.68 (1H, t, J=2.5Hz), 3.72 (3H, s), 3.90-4.07 (2H, m), 4.64 (1H, brs), 6.02 (1H, brs),6.86-7.16 (3H, m).

Example 21N-((2R,3S)-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamideA) 8-(2,3,6-trifluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene

To a mixed solution of8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dioxaspiro[4.5]dec-7-ene(1 g), 2-bromo-1,3,4-trifluorobenzene (1.189 g), and sodium hydrogencarbonate (0.631 g) in DME (15 ml)-water (3.00 ml) was added PdCl₂(dppf)(0.275 g) at room temperature. The mixture was heated under reflux at100° C. under a nitrogen atmosphere overnight. The mixture was filteredthrough celite, and the filtrate was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel chromatography (ethylacetate/hexane) to give the title compound (0.970 g).

MS, found: 271.0.

B) 8-(2,3,6-trifluorophenyl)-1,4-dioxaspiro[4.5]decane

To a solution of 8-(2,3,6-trifluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene(6.94 g) in ethanol (60 ml) was added 10% palladium/carbon (2.73 g) atroom temperature. The mixture was stirred at room temperature under ahydrogen atmosphere for 7 hr. The mixed solution was filtered, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel chromatography (ethyl acetate/hexane) to give the titlecompound (4.23 g).

MS, found: 273.0.

C) 4-(2,3,6-trifluorophenyl)cyclohexanone

To a mixed solution of8-(2,3,6-trifluorophenyl)-1,4-dioxaspiro[4.5]decane (6.49 g) in acetone(100 ml) and water (20 ml) was added 6 mol/l hydrochloric acid (7.95 ml)at room temperature. The mixture was stirred at 70° C. for 1 hr. Thesolvent was evaporated under reduced pressure, saturated brine was addedto the mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel chromatography (ethyl acetate/hexane) to give the titlecompound (5.24 g).

MS, found: 229.1.

D) cis-4-(2,3,6-trifluorophenyl)cyclohexanol

To a solution of 4-(2,3,6-trifluorophenyl)cyclohexanone (3.98 g) in THF(50 ml) was added lithium tri(sec-butyl)borohydride 1 mol/l THF solution(22.67 ml) at −78° C. The mixture was stirred at −78° C. under anitrogen atmosphere for 1 hr. To the mixture was added dropwise 30%hydrogen peroxide water at −78° C., and the mixture was warmed to roomtemperature and stirred for 5 min. To the reaction mixture was addedwater, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated aqueous ammonium chloride solution,dried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gelchromatography (ethyl acetate/hexane) to give the title compound (3.66g).

¹H NMR (300 MHz, CDCl₃) δ 1.39 (1H, d, J=3.0 Hz), 1.54 (1H, d, J=2.7Hz), 1.58-1.74 (3H, m), 1.84-1.98 (2H, m), 2.15-2.37 (2H, m), 3.02 (1H,tt, J=12.6, 3.3 Hz), 4.11-4.19 (1H, m), 6.76 (1H, tdd, J=9.5, 4.2, 2.3Hz), 6.95 (1H, qd, J=9.1, 4.9 Hz).

E)3-bromo-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)pyridin

A solution of cis-4-(2,3,6-trifluorophenyl)cyclohexanol (3.66 g) in THF(100 ml) was cooled to 0° C., 60% sodium hydride (1.272 g) was added,and the mixture was stirred under a calcium chloride tube dry atmosphereat room temperature for 10 min. To the reaction mixture was added3-bromo-2-(chloromethyl)pyridine (4.92 g), and the mixture was stirredat 70° C. for 3 hr. Water was added to the mixture at room temperature,and the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure. The residue waspurified by silica gel chromatography (ethyl acetate/hexane) to give thetitle compound (3.73 g).

MS, found: 401.0, 403.0.

F)N-(2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide

To a mixed solution of3-bromo-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)pyridine(4.0 g), methanesulfonamide (1.901 g),di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.424 g),and cesium carbonate (6.51 g) in DME (100 ml) was addedtris(dibenzylideneacetone)dipalladium(0) (0.915 g) at room temperature.The mixture was heated under reflux at 100° C. under a nitrogenatmosphere overnight. The reaction mixture was filtered through celite,and the filtrate was washed with water and saturated brine, dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel chromatography (ethylacetate/hexane) to give the title compound (3.97 g).

MS, found: 415.2.

G)N-((2R,3S)-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

To a mixed solution ofN-(2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide(3.95 g) in ethanol (100 ml) and acetic acid (11.11 ml) was added 5%rhodium/carbon (3.92 g) at room temperature. The mixture was stirred atroom temperature under a hydrogen atmosphere for 6 hr. The mixedsolution was filtered, and the solvent was evaporated under reducedpressure. The residue was dissolved in ethyl acetate-hexane, and theresulting precipitate was collected by filtration. The obtainedprecipitate was dissolved in saturated aqueous sodium hydrogen carbonatesolution, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was separated by HPLC (column: CHIRALPAK AD(AF003), 50 mmID×500mmL, manufactured by Daicel Corporation, mobile phase:hexane/2-propanol/diethylamine=700/300/1), and a fraction having ashorter retention time was obtained as the title compound (1.02 g)

¹H NMR (300 MHz, CDCl₃) δ 1.39-1.85 (12H, m), 1.89-2.04 (2H, m),2.06-2.24 (2H, m), 2.70 (1H, td, J=11.7, 2.7 Hz), 2.92 (1H, ddd, J=8.2,4.4, 2.1 Hz), 3.00-3.14 (2H, m), 3.33-3.43 (1H, m), 3.45-3.55 (1H, m),3.63 (2H, d, J=2.3 Hz), 5.37 (1H, brs), 6.68-6.80 (1H, m), 6.94 (1H, qd,J=9.1, 4.9 Hz).

Example 22N-((2R,3S)-1-acetyl-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

To a solution ofN-((2R,3S)-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(900 mg) and triethylamine (0.893 ml) in THF (15 ml) was added acetylchloride (0.303 ml) at room temperature, and the mixture was stirred for1 hr. Water was added to the mixture at room temperature, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel chromatography (ethyl acetate/hexane) to give the titlecompound (920 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.45-1.57 (3H, m), 1.58-1.69 (3H, m),1.74-2.10 (6H, m), 2.18 (2H, s), 2.97-3.06 (4H, m), 3.06-3.30 (1H, m),3.51-3.79 (4H, m), 3.81-3.96 (1H, m), 4.24-4.64 (1H, m), 4.98-5.28 (1H,m), 5.67 (1H, d, J=8.7 Hz), 6.68-6.82 (1H, m), 6.88-7.03 (1H, m).

Example 23N-((2R,3S)-2-(((cis-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamideA) cis-4-(2-(trifluoromethyl)phenyl)cyclohexanol

To a solution of 4-(2-(trifluoromethyl)phenyl)cyclohexanone (2.56 g) inTHF (50 ml) was added dropwise over 4 min at −78° C. lithiumtri(sec-butyl)borohydride 1 mol/l THF solution (13.74 ml). The mixturewas stirred at −78° C. for 2 hr, and at 0° C. overnight. To the mixturewere added dropwise acetone, water and 30% hydrogen peroxide water at 0°C., and the mixture was stirred at room temperature for 1 hr, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, dried over anhydrous magnesium sulfate,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel chromatography (ethyl acetate/hexane) to give thetitle compound (2.13 g).

¹H NMR (300 MHz, CDCl₃) δ 1.31 (1H, d, J=2.3 Hz), 1.58-1.79 (4H, m),1.83-2.01 (4H, m), 2.95 (1H, t, J=11.2 Hz), 4.14-4.25 (1H, m), 7.22-7.31(1H, m), 7.46-7.65 (3H, m).

B)3-bromo-2-(((cis-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)pyridine

To a solution of cis-4-(2-(trifluoromethyl)phenyl)cyclohexanol (9.36 g)in THF (150 ml) was added at 0° C. potassium hexamethyl disilazide 1.0mol/l tert-butyl methyl ether solution (57.5 ml), and the mixture wasstirred for 30 min. To the reaction mixture was added3-bromo-2-(bromomethyl)pyridine (19.26 g), and the mixture was stirredunder a calcium chloride tube dry atmosphere at 60° C. for 5 hr,potassium carbonate (15.89 g) and 2-mercaptoacetic acid (5.32 ml) wereadded at room temperature, and the mixture was stirred overnight. Waterwas added to the mixture at room temperature, and the mixture wasextracted with ethyl acetate. The organic layer was washed with 1 mol/laqueous sodium hydroxide solution and saturated brine, dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by NH silica gelchromatography and silica gel column chromatography (ethylacetate/hexane) to give the title compound (3.87 g).

MS, found: 414.1, 416.1.

C)N-(2-(((cis-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide

To a solution of3-bromo-2-(((cis-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)pyridine(3.87 g) in DME (25 ml) were added methanesulfonamide (1.066 g),di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.159 g),tris(dibenzylideneacetone)dipalladium(0) (0.171 g) and cesium carbonate(4.57 g) at room temperature. The mixture was stirred at 80° C. under anitrogen atmosphere overnight. Water was added to the reaction mixtureat room temperature, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel chromatography (ethylacetate/hexane) to give the title compound (3.85 g).

MS, found: 429.2.

D)N-((2R,3S)-2-(((cis-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

A mixture ofN-(2-(((cis-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide(0.93 g), 5% rhodium/carbon (0.893 g), ethanol (27 ml) and acetic acid(3.00 ml) was stirred at room temperature under a hydrogen atmospherefor 11 hr. The mixture was filtered, and the solvent was evaporatedunder reduced pressure. The residue was dissolved in ethyl acetate, theorganic layer was washed with 1 mol/l aqueous sodium hydroxide solutionand saturated brine, dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was washedwith IPE, and recrystallized from ethanol/hexane to give a white solid(361 mg). The mother liquor was concentrated under reduced pressure. Theresidue was purified by NH silica gel chromatography (ethylacetate/hexane) to give a white solid (208 mg). The obtained whitesolids (361 mg and 208 mg) were combined, and separated by HPLC (column:CHIRALPAK AD(LF001), 50 mmID×500 mmL, manufactured by DaicelCorporation, mobile phase: hexane/2-propanol/diethylamine=900/100/1),and a fraction having a shorter retention time was obtained as the titlecompound (0.257 g).

¹H NMR (300 MHz, CDCl₃) δ 1.51 (2H, brs), 1.57-1.88 (8H, m), 2.03 (3H,d, J=13.0 Hz), 2.71 (1H, td, J=12.0, 2.8 Hz), 2.86-2.96 (2H, m), 2.99(3H, s), 3.09 (1H, d, J=11.0 Hz), 3.39 (1H, dd, J=9.3, 7.8 Hz), 3.54(1H, dd, J=9.5, 4.5 Hz), 3.60-3.69 (2H, m), 5.35 (1H, d, J=7.6 Hz),7.27-7.33 (1H, m), 7.43-7.54 (2H, m), 7.61 (1H, s).

Example 24N-((2R,3S)-1-acetyl-2-(((cis-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

To a solution ofN-((2R,3S)-2-(((cis-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(97.2 mg) and triethylamine (0.094 ml) in THF (5 ml) was added aceticanhydride (0.042 ml) at room temperature, and the mixture was stirredunder a calcium chloride tube dry atmosphere overnight. Water was addedto the mixture at room temperature, and the mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography and NH silica gel column chromatography (ethylacetate/hexane) to give the title compound (87.8 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.48-2.31 (14H, m), 2.50-3.22 (5H, m),3.31-3.79 (3H, m), 3.84-4.06 (1H, m), 4.30-4.65 (1H, m), 5.17 (1H, dt,J=9.0, 4.4 Hz), 5.63 (1H, brs), 6.31 (1H, d, J=7.6 Hz), 7.20-7.29 (1H,m), 7.47-7.64 (3H, m).

Example 25N-((2R,3S)-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)-1-glycoloylpiperidin-3-yl)methanesulfonamide

To a solution ofN-((2R,3S)-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(100.2 mg) in pyridine (2 ml) was added 2-chloro-2-oxoethyl acetate (51mg) at room temperature. The mixture was stirred under a calciumchloride tube dry atmosphere at the same temperature overnight. To thereaction mixture was added 1 mol/l hydrochloric acid at roomtemperature, and the mixture was extracted with ethyl acetate. Theextract was successively washed with saturated aqueous sodium hydrogencarbonate solution, and saturated brine, dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was dissolved in methanol (2 ml), 1 mol/l aqueous sodiumhydroxide solution (1.25 ml) was added at 0° C., and the mixture wasstirred at room temperature for 1 hr. To the reaction mixture was addedwater at room temperature, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (104 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.58-2.23 (11H, m), 2.70-3.00 (2H, m), 3.01(3H, s), 3.05-3.37 (1H, m), 3.44-4.00 (5H, m), 4.01-4.62 (3H, m),4.79-5.29 (1H, m), 5.89 (1H, d, J=7.95 Hz), 6.81-7.15 (3H, m).

Example 26N-(cis-2-(((cis-4-(2-methoxyphenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamideA) 8-(2-methoxyphenyl)-1,4-dioxaspiro[4.5]dec-7-ene

To a mixed solution of 1,4-dioxaspiro[4.5]dec-7-en-8-yltrifluoromethanesulfonate (3.00 g), (2-methoxyphenyl)boronic acid (2.37g), sodium carbonate (4.41 g) and lithium chloride (22 mg) in DME (40ml)/water (10 ml) was added tetrakis(triphenylphosphine)palladium(0)(601 mg), and the mixture was stirred under a nitrogen atmosphere at 90°C. for 2 hr. To the reaction mixture was added water, and the mixturewas extracted with ethyl acetate. The obtained organic layer was washedsuccessively with saturated aqueous sodium hydrogen carbonate solutionand saturated brine, dried over anhydrous magnesium sulfate and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (1.60 g).

MS, found: 247.1.

B) 4-(2-methoxyphenyl)cyclohexanone

To a solution of 8-(2-methoxyphenyl)-1,4-dioxaspiro[4.5]dec-7-ene (1.60g) in ethanol (25 ml) was added 10% palladium/carbon (346 mg), and themixture was stirred under a hydrogen atmosphere (normal pressure) atroom temperature for 2 hr. The reaction mixture was filtered, and thefiltrate was concentrated under reduced pressure. To a solution of theresidue in acetone (15 ml) was added 2 mol/l hydrochloric acid (15 ml),and the mixture was stirred at 60° C. for 2 hr. The reaction mixture wasextracted with ethyl acetate. The obtained organic layer was washedsuccessively with saturated aqueous sodium hydrogen carbonate solutionand saturated brine, dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (1.02 g).

MS, found: 205.1.

C) cis-4-(2-methoxyphenyl)cyclohexanol

Under a nitrogen atmosphere, to a solution of4-(2-methoxyphenyl)cyclohexanone (1.00 g) in THF (20 ml) was addeddropwise lithium tri(sec-butyl)borohydride 1 mol/l THF solution (6.4 ml)at 0° C., and the mixture was stirred at the same temperature for 1 hr.To the reaction mixture were successively added water and 30% hydrogenperoxide water at 0° C., and the mixture was stirred at the sametemperature for 5 min and extracted with ethyl acetate. The obtainedorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (893 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.36-1.59 (4H, m), 1.66-1.87 (4H, m),2.80-2.95 (1H, m), 3.76 (3H, s), 3.86-3.94 (1H, m), 4.22-4.39 (1H, m),6.76-7.00 (2H, m), 7.04-7.27 (2H, m).

D) 3-bromo-2-(((cis-4-(2-methoxyphenyl)cyclohexyl)oxy)methyl)pyridine

To a solution of cis-4-(2-methoxyphenyl)cyclohexanol (889 mg) in THF (20ml) was added 60% sodium hydride (345 mg) at 0° C., and the mixture wasstirred at under a nitrogen atmosphere at room temperature for 2 hr. Tothe reaction mixture was added 3-bromo-2-(chloromethyl)pyridine (1.16g), and the mixture was stirred at room temperature for 2 hr, and at 70°C. for 3 hr. To the reaction mixture was added water, and the mixturewas extracted with ethyl acetate. The obtained organic layer was washedsuccessively with water and saturated brine, dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound (743 mg).

MS, found: 376.0, 378.0.

E)N-(2-(((cis-4-(2-methoxyphenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide

A mixture of3-bromo-2-(((cis-4-(2-methoxyphenyl)cyclohexyl)oxy)methyl)pyridine (740mg), methanesulfonamide (224 mg),di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (100 mg),tris(dibenzylideneacetone)dipalladium(0) (90 mg), cesium carbonate (961mg) and DME (10 ml) was heated under reflux under a nitrogen atmospherefor 6 hr. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The obtained organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate, and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane) to give thetitle compound (723 mg).

MS, found: 391.2.

F)N-(cis-2-(((cis-4-(2-methoxyphenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

To a mixed solution ofN-(2-(((cis-4-(2-methoxyphenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide(669 mg) in ethanol (9 ml)/acetic acid (1 ml) was added 5%rhodium/carbon (705 mg), and the mixture was stirred under a hydrogenatmosphere (normal pressure) at room temperature for 20 hr.Rhodium/carbon was filtered off, toluene was added, and the solvent wasevaporated under reduced pressure. The residue was washed withdiisopropyl ether, and the obtained solid was dissolved in ethylacetate. Saturated aqueous sodium hydrogen carbonate solution was added,and the aqueous layer was extracted with ethyl acetate. The combinedorganic layers were washed successively with water and saturated brine,dried over anhydrous magnesium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by NH silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (123mg).

¹H NMR (300 MHz, CDCl₃) δ 1.48-1.89 (9H, m), 1.94-2.11 (4H, m),2.59-2.76 (1H, m), 2.84-3.15 (6H, m), 3.28-3.43 (1H, m), 3.45-3.54 (1H,m), 3.56-3.69 (2H, m), 3.82 (3H, s), 5.27-5.54 (1H, m), 6.81-6.88 (1H,m), 6.89-6.98 (1H, m), 7.09-7.24 (2H, m).

Example 27N-((2R,3S)-2-(((cis-4-(2-methoxyphenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

N-(cis-2-(((cis-4-(2-methoxyphenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(2.0 g) was separated by HPLC (column: CHIRALPAK AD(AF003), 50 mmID×500mmL, manufactured by Daicel Corporation, mobile phase:hexane/2-propanol/diethylamine=700/300/1), and a fraction having ashorter retention time was obtained as the title compound (783 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.45-1.83 (9H, m), 1.90-2.10 (4H, m),2.62-2.76 (1H, m), 2.86-3.13 (6H, m), 3.32-3.42 (1H, m), 3.46-3.55 (1H,m), 3.56-3.68 (2H, m), 3.82 (3H, s), 5.30-5.51 (1H, m), 6.82-6.88 (1H,m), 6.88-6.97 (1H, m), 7.10-7.24 (2H, m).

Example 28N-((2R,3S)-1-(cyclopropylcarbonyl)-2-(((cis-4-(2-methoxyphenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

To a solution ofN-((2R,3S)-2-(((cis-4-(2-methoxyphenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(200 mg) and triethylamine (102 mg) in THF (5 ml) was addedcyclopropanecarbonyl chloride (79 mg) at room temperature, and themixture was stirred at the same temperature for 30 min. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The extract was washed with saturated brine, dried overanhydrous magnesium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (227mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.57-0.87 (4H, m), 1.31-1.81 (10H, m),1.83-2.07 (3H, m), 2.56-3.07 (4H, m), 3.10-3.88 (8H, m), 3.99-5.01 (2H,m), 6.80-7.39 (5H, m).

Example 29 isopropylcis-3-((dimethylsulfamoyl)amino)-2-(((1-(pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)piperidine-1-carboxylateA) tert-butyl 4-((3-bromopyridin-2-yl)methoxy)piperidine-1-carboxylate

A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (9.63 g) inTHF (100 ml) was cooled to 0° C., 60% sodium hydride (3.19 g) was added,and the mixture was stirred for 20 min. To the reaction mixture wasadded a solution of 3-bromo-2-(bromomethyl)pyridine (10.00 g) in THF(100 ml), and the mixture was stirred at room temperature under an argonatmosphere overnight. To the mixture was added water at 0° C., and themixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, dried over anhydrous magnesium sulfate,and the solvent was evaporated under reduced pressure. The residue waspurified by silica gel chromatography (ethyl acetate/hexane) to give thetitle compound (13.12 g).

MS, found: 371.1, 373.1.

B) tert-butyl4-((3-((dimethylsulfamoyl)amino)pyridin-2-yl)methoxy)piperidine-1-carboxylate

To a mixed solution of tert-butyl4-((3-bromopyridin-2-yl)methoxy)piperidine-1-carboxylate (5 g),N,N-dimethylsulfuric acid diamide (2.007 g),di-tert-butyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.686 g),and cesium carbonate (6.58 g) in DME (50 ml) was addedtris(dibenzylideneacetone)dipalladium(0) (0.617 g) at room temperature.The mixture was heated under reflux at 100° C. under an argon atmospherefor 20 hr. The reaction mixture was neutralized with 1 mol/lhydrochloric acid, and extracted with ethyl acetate. The organic layerwas washed with saturated brine, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel chromatography(ethyl acetate/hexane, methanol/ethyl acetate) and NH silica gelchromatography (ethyl acetate/hexane) to give the title compound (4.10g).

MS, found: 415.2.

C) tert-butyl4-((cis-3-((dimethylsulfamoyl)amino)piperidin-2-yl)methoxy)piperidine-1-carboxylate

To a mixed solution of tert-butyl4-((3-((dimethylsulfamoyl)amino)pyridin-2-yl)methoxy)piperidine-1-carboxylate(4.00 g) in ethanol (100 ml) and acetic acid (10.00 ml) was added 5%rhodium/carbon (3.97 g) at room temperature. The mixture was stirred atroom temperature under a hydrogen atmosphere overnight. The mixedsolution was filtered, and the solvent was evaporated under reducedpressure. To the residue were added ethyl acetate and hexane and theprecipitated solid was collected by filtration. The obtained solid wasdissolved in saturated aqueous sodium hydrogen carbonate solution, andthe mixture was extracted with ethyl acetate. The organic layer wasdried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure to give the title compound (1.870 g).

MS, found: 421.2.

D) isopropylcis-2-(((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)methyl)-3-((dimethylsulfamoyl)amino)piperidine-1-carboxylate

To a solution of tert-butyl4-((cis-3-((dimethylsulfamoyl)amino)piperidin-2-yl)methoxy)piperidine-1-carboxylate(100 mg) and N,N-diisopropylethylamine (0.164 ml) in THF (3 ml) wasadded isopropyl chloroformate (29.1 mg) at room temperature, and themixture was stirred for 2 days. Water was added to the mixture at roomtemperature, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel chromatography (ethylacetate/hexane) to give the title compound (120 mg).

MS, found: 407.2.

E) isopropyl cis-3-((dimethylsulfamoyl)amino)-2-((piperidin-4-yloxy)methyl) piperidine-1-carboxylate hydrochloride

To isopropylcis-2-(((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)methyl)-3-((dimethylsulfamoyl)amino)piperidine-1-carboxylate(120 mg) was added 4 mol/l hydrogen chloride ethyl acetate solution (5ml) at room temperature, and the mixture was stirred for 2 hr. Thesolvent in the mixture was evaporated under reduced pressure to give thetitle compound (106 mg).

MS, found: 407.2.

F) isopropylcis-3-((dimethylsulfamoyl)amino)-2-(((1-(pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)piperidine-1-carboxylate

To a solution of isopropylcis-3-((dimethylsulfamoyl)amino)-2-((piperidin-4-yloxy)methyl)piperidine-1-carboxylatehydrochloride (106 mg) and cesium carbonate (235 mg) in NMP (2 ml) wasadded 2-chloropyrimidine (41.2 mg), and the mixture was stirred at 90°C. for 2 hr. Water was added to the mixture at room temperature, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel chromatography (ethyl acetate/hexane) to give the titlecompound (89 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.24 (3H, s), 1.26 (3H, s), 1.42-1.58 (2H, m),1.60-1.66 (1H, m), 1.67-1.79 (2H, m), 1.88-2.00 (2H, m), 2.00-2.11 (1H,m), 2.69-2.78 (1H, m), 2.80 (6H, s), 3.35-3.54 (3H, m), 3.62 (1H, tt,J=8.2, 3.9 Hz), 3.70 (1H, dd, J=9.7, 4.4 Hz), 3.96 (2H, dd, J=9.8, 8.3Hz), 4.26 (2H, dt, J=13.3, 5.1 Hz), 4.46-4.69 (1H, m), 4.93 (1H, spt,J=6.2 Hz), 5.51 (1H, d, J=8.0 Hz), 6.47 (1H, t, J=4.7 Hz), 8.29 (2H, d,J=4.5 Hz).

Example 30(2R,3S)—N-ethyl-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxamide

To a solution ofN-[cis-2-(4-phenyl-cyclohexyloxymethyl)-piperidin-3-yl]-methanesulfonamide(280 mg), triethylamine (0.319 ml) in THF (2 ml) was addedethylisocyanate (81 mg) at 0° C., and the mixture was stirred at roomtemperature overnight. To the reaction mixture was added water, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane). The obtainedcompound was separated by HPLC (column: CHIRALPAK IC(ME001), 50 mmID×500mmL, manufactured by Daicel Corporation, mobile phase:hexane/2-propanol=200/800), and a fraction having a longer retentiontime was obtained as the title compound (153 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.14 (3H, t, J=7.2 Hz), 1.56-1.80 (9H, m),1.98-2.10 (3H, m), 2.45-2.59 (1H, m), 2.84 (1H, qd, J=12.7, 2.8 Hz),3.01 (3H, s), 3.26 (2H, qd, J=7.2, 5.3 Hz), 3.52-3.81 (4H, m), 3.93 (1H,dd, J=9.2, 7.7 Hz), 4.48-4.59 (1H, m), 4.70 (1H, t, J=5.1 Hz), 5.74 (1H,d, J=7.7 Hz), 7.14-7.35 (5H, m).

Example 31N-((2R,3S)-1-(cyclopropylcarbonyl)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

To a solution ofN-((2R,3S)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(58 mg), triethylamine (0.044 ml) in THF (3 ml) was addedcyclopropanecarbonyl chloride (0.022 ml) at room temperature, and themixture was stirred under a calcium chloride tube dry atmosphereovernight. To the reaction mixture was added water, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (62 mg).

¹H NMR (300 MHz, CDCl₃) δ 0.74-0.85 (2H, m), 0.94-1.05 (2H, m),1.58-1.88 (10H, m), 2.01-2.23 (3H, m), 2.45-2.63 (1H, m), 2.92-3.18 (4H,m), 3.41-3.77 (3H, m), 3.89-4.60 (2H, m), 4.69-5.23 (1H, m), 5.46-6.39(1H, m), 7.13-7.25 (3H, m), 7.27-7.34 (2H, m).

Example 32 methyl(2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)piperidine-1-carboxylate

To a solution ofN-((2R,3S)-2-(((cis-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(51.2 mg) and triethylamine (0.049 ml) in THF (2 ml) was added methylchloroformate (0.018 ml) at room temperature, and the mixture wasstirred under a calcium chloride tube dry atmosphere overnight. Waterwas added to the mixture at room temperature, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel chromatography (ethyl acetate/hexane) to give the titlecompound (56.3 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.55-1.89 (9H, m), 1.97-2.19 (3H, m), 2.80(1H, td, J=13.3, 3.0 Hz), 2.88-3.10 (4H, m), 3.44-3.71 (3H, m),3.72-3.78 (3H, m), 4.02 (2H, t, J=9.1 Hz), 4.67 (1H, brs), 6.15 (1H,brs), 7.19-7.31 (1H, m), 7.47-7.67 (3H, m).

Example 340N-((2R,3S)-1-glycoloyl-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

To a mixture ofN-((2R,3S)-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide(100.8 mg) and pyridine (2.0 ml) was added 2-chloro-2-oxoethyl acetate(49.1 mg) at room temperature. The mixture was stirred at roomtemperature overnight. To the mixture was added 1 mol/l hydrochloricacid at room temperature, and the mixture was extracted with ethylacetate. The organic layer was separated, washed with saturated aqueoussodium hydrogen carbonate solution and saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. To amixture of the residue and methanol (2.0 ml) was added 1 mol/l aqueoussodium hydroxide solution at 0° C. The mixture was stirred at roomtemperature for 1 hr. Water was added to the mixture at roomtemperature, and the mixture was extracted with ethyl acetate. Theorganic layer was separated, washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (108.1 mg).

¹H NMR (300 MHz, CDCl₃) δ 1.48-1.68 (6H, m), 1.85-2.19 (6H, m),2.75-3.12 (4H, m), 3.13-3.89 (6H, m), 3.93-4.66 (3H, m), 4.87-5.16 (1H,m), 5.40 (1H, d, J=8.7 Hz), 6.66-6.83 (1H, m), 6.96 (1H, qd, J=9.1, 4.9Hz).

The compounds of Examples 33-339 and 341-372 were produced according tothe aforementioned production methods, a method shown in the Examples,or a method analogous thereto. The Example compounds produced are shownin the following Tables. In the Tables, MS shows measured values.

TABLE 1-1 Ex. No. IUPAC name Structure MS 1 N-(cis-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

333.2 2 (2R,3S)-N-ethyl-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-3-((methylsulfonyl)amino)piperidine- 1-carboxamide

404.2 3 N-((2R,3S)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)-piperidin-3-yl)methanesulfonamide

367.1 4 N-((2R,3S)-1-acetyl-2-(((cis-4- phenylcyclohexyl)oxy)methyl)-piperidin-3-yl)methanesulfonamide

409.2 5 methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)- piperidine-1-carboxylate

425.1 6 N-(cis-2-(((cis-4-(3,5- difluorophenyl)cyclohexyl)oxy)-methyl)piperidin-3- yl)methanesulfonamide acetate

403.2

TABLE 1-2 Ex. No. IUPAC name Structure MS 7 N-((2R,3S)-2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)- methyl)piperidin-3-yl)methanesulfonamide

403.2 8 N-((2R,3S)-1-acetyl-2-(((cis-4- (3,5-difluorophenyl)cyclohexyl)oxy)- methyl)piperidin-3-yl)methanesulfonamide

445.3 9 N-(cis-2-(((cis-4-(2,5- difluorophenyl)cyclohexyl)oxy)-methyl)piperidin-3- yl)methanesulfonamide

403.2 10 N-((2R,3S)-2-(((cis-4-(2,5- difluorophenyl)cyclohexyl)oxy)-methyl)piperidin-3- yl)methanesulfonamide

403.2 11 methyl (2R,3S)-2-(((cis-4-(2,5- difluorophenyl)cyclohexyl)oxy)-methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylate

461.2 12 N-(cis-2-(((cis-4-(2,6- difluorophenyl)cyclohexyl)oxy)-methyl)piperidin-3- yl)sulfonamide

403.2

TABLE 1-3 Ex. No. IUPAC name Structure MS 13 N-((2R,3S)-2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)- methyl)piperidin-3-yl)methanesulfonamide

403.2 14 N-((2R,3S)-l-acetyl-2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)- methyl)piperidin-3-yl)methanesulfonamide

445.2 15 N-((2R,3S)-2-(((cis-4-(3- fluorophenyl)cyclohexyl)oxy)-methyl)piperidin-3- yl)methanesulfonamide

385.1 16 N-((2R,3S)-1-(cyclopropylcarbonyl)- 2-(((cis-4-(3-fluorophenyl)cyclohexyl)oxy)- methyl)piperidin-3- yl)methanesulfonamide

453.2 17 N-(cis-2-(((cis-4-(2,3- difluorophenyl)cyclohexyl)oxy)-methyl)piperidin-3- yl)methanesulfonamide

403.1 18 N-((2R,3S)-2-(((cis-4-(2,3- difluorophenyl)cyclohexyl)oxy)-methyl)piperidin-3- yl)methanesulfonamide

403.2

TABLE 1-4 Ex. No. IUPAC name Structure MS 19N-((2R,3S)-1-acetyl-2-(((cis-4- (2,3- difluorophenyl)cyclohexyl)oxy)-methyl)piperidin-3- yl)methanesulfonamide

445.2 20 methyl (2R,3S)-2-(((cis-4-(2,3- difluorophenyl)cyclohexyl)oxy)-methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylate

459.2 21 N-((2R,3S)-2-(((cis-4-(2,3,6- trifluorophenyl)cyclohexyl)oxy)-methyl)piperidin-3- yl)methanesulfonamide

421.1 22 N-((2R,3S)-1-acetyl-2-(((cis-4- (2,3,6-trifluorophenyl)cyclohexyl)oxy)- methyl)piperidin-3-yl)methanesulfonamide

463.2 23 N-((2R,3S)-2-(((cis-4-(2- (trifluoromethyl)phenyl)-cyclohexyl)oxy)methyl)piperidin-3- yl)methanesulfonamide

435.1 24 N-((2R,3S)-1-acetyl-2-(((cis-4-(2- (trifluoromethyl)phenyl)-cyclohexyl)oxy)methyl)piperidin-3- yl)methanesulfonamide

477.2

TABLE 1-5 Ex. No. IUPAC name Structure MS 25 N-((2R,3S)-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)- methyl)-1-glycoloylpiperidin-3-yl)methanesulfonamide

461.2 26 N-(cis-2-(((cis-4-(2- methoxyphenyl)cyclohexyl)oxy)-methyl)piperidin-3- yl) methanesulfonamide

397.2 27 N-((2R,3S)-2-(((cis-4-(2- methoxyphenyl)cyclohexyl)oxy)-methyl)piperidin-3- yl)methanesulfonamide

397.2 28 N-((2R,3S)-1-(cyclopropylcarbonyl) 2-(((cis-4-(2-methoxyphenyl)cyclohexyl)oxy)- methyl)piperidin-3- yljmethanesulfonamide

465.2 29 isopropyl cis-3- ((dimethylsulfamoyl)amino)-2-(((1-(pyrimidin-2-yl)piperidin-4- yl)oxy)methyl)piperidine-1- carboxylate

485.2 30 (2R,3S)-N-ethyl-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl) - piperidine-1-carboxamide

438.3

TABLE 1-6 Ex. No. IUPAC name Structure MS 31N-((2R,3S)-1-(cyclopropylcarbonyl)- 2-(((cis-4-phenylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

435.2 32 methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-(2-(trifluoromethyl)phenyl)- cyclohexyl)oxy)methyl)piperidine-1-carboxylate

493.2 33 N-((2R,3S)-1-acetyl-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)- piperidin-3-yl)ethanesulfonamide

389.2 34 N-(cis-1-benzoyl-2-(((cis-4- methylcyclohexyl)oxy)methyl)-piperidin-3-yl)ethanesulfonamide

423.2 35 N-(cis-1-butyryl-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-piperidin-3-yl)methanesulfonamide

403.2 36 N-(cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-1-(methylsulfonyl)piperidin-3- yl)methanesulfonamide

409.2

TABLE 1-7 Ex. No. IUPAC name Structure MS 37cis-3-((ethylsulfonyl)amino)-2 (((cis-4- methylcyclohexyl)oxy)methyl)-Nphenylpiperidine-1-carboxamide

438.1 38 N-(cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-1(morpholin-4-ylcarbonyl)piperidin 3-yl)methanesulfonamide

446.2 39 N-(cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-1-(pyrrolidin-1-ylcarbonyl)piperidin- 3-yl)methanesulfonamide

430.2 40 cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-N,N-dimethyl-3- ((methylsulfonyl)amino)piperidine- 1-carboxamide

404.2 41 benzyl cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-3((methylsulfonyl)amino)piperidine 1-carboxylate

465.1 42 ethyl cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-3((methylsulfonyl)amino)piperidine 1-carboxylate

403.2

TABLE 1-8 Ex. No. IUPAC name Structure MS 43 phenyl cis-2- (((cis-4-isopropylcyclohexyl)oxy)methyl)-3 ((methylsulfonyl)amino)piperidine1-carboxylate

453.2 44 N-(cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-1-(phenoxyacetyl)piperidin-3- yl)methanesulfonamide

467.2 45 N-(cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-1-(methoxyacetyl)piperidin-3- yl)methanesulfonamide

405.2 46 N-(cis-1-(2-furoyl)-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

427.2 47 2-(cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-3-((methylsulfonyl)amino)piperidin-1- yl)-2-oxoethyl acetate

431.1 48 N-(cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-1-(1,2-oxazol-5-ylcarbonyl)piperidin- 3-yl) methanesulfonainide

426.2

TABLE 1-9 Ex. No. IUPAC name Structure MS 49N-(cis-1-(4-fluorobenzoyl)-2- ( ((cis-4-isopropylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

453.1 50 N-(cis-1-(4-chlorobenzoyl)-2- (((cis-4-isopropylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

469.1 51 N-(cis-1-(biphenyl-4-ylcarbonyl)-2 (((cis-4-isopropylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

513.2 52 N-(cis-l-(2,2,3,3,4,4,4- heptafluorobutanoyl)-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

527.1 53 N-(cis-1-(2,2-dimethylpropanoyl)-2 (((cis-4-isopropylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

415.1 54 N-(cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-(3-phenylpropanoyl)piperidin-3- yl)methanesulfonamide

465.2

TABLE 1-10 Ex. No. IUPAC name Structure MS 55 methyl4-(cis-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)-3- ((methylsulfonyl)amino)piperidin-1-yl)-4-oxobutanoate

447.2 56 N-(cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-1-(2-thienylcarbonyl)piperidin-3- yl)methanesulfonamide

441.1 57 N-(cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-1-(pyridin-3-ylcarbonyl)piperidin-3 yl)methanesulfonamide

438.2 58 N-(cis-1-isonicotinoyl-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

438.1 59 N-(cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-1-((1-methyl-1H-pyrazol-4- yl)carbonyl)piperidin-3- yl)methanesulfonamide

441.3 60 N-(cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-1-(tetrahydro-2H-pyran-4- ylcarbonyl)piperidin-3- yl)methanesulfonamide

445.3

TABLE 1-11 Ex. No. IUPAC name Structure MS 61 cis-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)- N,N-dimethyl-3-((methylsulfonyl)amino)piperidine- 1-sulfonamide

438.1 62 N-(cis-1-(cyclopropylsulfonyl)-2- (((cis-4-isopropylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

435.1 63 N-(cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-1-(2-thienylsulfonyl)piperidin-3- yl)methanesulfonamide

477 64 N-(cis-1-((4- chlorophenyl)sulfonyl)-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

505.1 65 N-(cis-1-((1,2-dimethyl-1H- imidazol-4-yl)sulfonyl)-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

491.2 66 N-(cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-1-(pyridin-3-ylsulfonyl)piperidin-3- yl)methanesulfonamide

474.2

TABLE 1-12 Ex. No. IUPAC name Structure MS 67 N-(cis-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)-1- ((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-3- yl)methanesulfonamide

475.1 68 N-(cis-1-(3,4-dihydro-2H-chromen-6- ylsulfonyl)-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

527.2 69 N-((2R,3S)-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-piperidin-3-yl)methanesulfonamide ((2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinate

333.1 70 N-((2R,3S)-1-acetyl-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

375.1 71 N-(cis-1-acetyl-2-(((1s,4s)-1,1′- bi(cyclohexyl)-4-yloxy)methyl)piperidin-3- yl)methanesulfonamide

415.1 72 N-(cis-1-(3-hydroxypropanoyl)-2- (((cis-4-isopropylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

405.2

TABLE 1-13 Ex. No. IUPAC name Structure MS 73 N-(cis-1-(3-hydroxy-3-methylbutanoyl)-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-piperidin-3-yl)methanesulfonamide

433.1 74 N-(cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-1-(3-(methylsulfonyl)- propanoyl)piperidin-3- yl)methanesulfonamide

467.2 75 N-(cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-1-(4-oxopentanoyl)piperidin-3- yl)methanesulfonamide

429.1 76 N-(cis-1-acetyl-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-piperidin-3-yl)propane-2- sulfonamide

403.1 77 N-(cis-1-acetyl-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-piperidin-3-yl)propane-1- sulfonamide

403.2 78 N′-(cis-1-acetyl-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-piperidin-3-yl)-N,N- dimethylsulfuric diamide

404.2

TABLE 1-14 Ex. No. IUPAC name Structure MS 79N-(cis-1-acetyl-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-piperidin-3-yl)-N′-ethylsulfuric diamide

404.2 80 N-(cis-1-acetyl-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-piperidin-3-yl)-1,1,1- trifluoromethanesulfonamide

429.2 81 N-(cis-1-acetyl-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-piperidin-3-yl)-2-methylpropane-1 sulfonamide

417.2 82 N-(cis-1-acetyl-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-piperidin-3-yl)-1- phenylmethanesulfonamide

451.2 83 N-(2-(cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-3-((methylsulfonyl)amino)piperidin-1- yl)-2-oxoethyl)acetamide

432.1 84 N-((2R,3S)-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-1-(((1-methyl-1H-pyrazol-3- yl)oxy)acetyl)piperidin-3-yl)methanesulfonamide

471.2

TABLE 1-15 Ex. No. IUPAC name Structure MS 85N-(cis-1-(N,N-dimethyl-beta- alanyl)-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

430.2 86 tert-butyl 3-((cis-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)-3- ((methylsulfonyl)amino)piperidin-1-yl)carbonyl)azetidine-1-carboxylate

514.1 87 N-(cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-1-(5-oxoprolyl)piperidin-3- yl)methanesulfonamide

444.2 88 N-(cis-1-(azetidin-3-ylcarbonyl)-2- (((cis-4-isopropylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

416.2 89 N-(cis-1-((l-acetylazetidin-3- yl)carbonyl)-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

458.2 90 N-(cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-((1-(methylsulfonyl)azetidin-3- yl)carbonyl)piperidin-3-yl)methanesulfonamide

494.2

TABLE 1-16 Ex. No. IUPAC name Structure MS 91 N-((2R,3S)-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)-1- ((3-oxocyclobutyl)carbonyl)piperidin-3- yl)methanesulfonamide

427.1 92 N-((2R,3S)-1-((3- hydroxycyclobutyl)carbonyl)-2- (((cis-4-isopropylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

431.2 93 N-(cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-1-((6-oxopyrimidin-1(6H)- yl)acetyl)piperidin-3- yl)methanesulfonamide

467 94 N-(cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-1-((4-oxopyridazin-1(4H)- yl)acetyl)piperidin-3- yl)methanesulfonamide

469.2 95 N-(cis-1-acetyl-2-(((cis-4-(2- fluoropropan-2-yl)cyclohexyl)oxy)methyl)piperidin- 3-yl)methanesulfonamide

391 96 cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-N-(2-methoxyethyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxamide

434.2

TABLE 1-17 Ex. No. IUPAC name Structure MS 97 cis-N-(2-hydroxyethyl)-2-(((cis-4 isopropylcyclohexyl)oxy)methyl)-3((methylsulfonyl)amino)piperidine 1-carboxamide

420.2 98 cis-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-3-((methylsulfonyl)amino)-N-(2,2,2- trifluoroethyl)piperidine-l-carboxamide

456 99 cis-N-cyclopropyl-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-3-((methylsulfonyl)amino)piperidine 1-carboxamide

416.2 100 cis-2-((icis-4- isopropylcyclohexyl)oxy)methyl)-3-((methylsulfonyl)amino)-N- propylpiperidine-1-carboxamide

418.2 101 cis-N-isopropyl-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-3((methylsulfonyl)amino)piperidine 1-carboxamide

418.2 102 (2R,3S)-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-N-methyl-3- ((methylsulfonyl)amino)piperidin 1-carboxamide

390.2

TABLE 1-18 Ex. No. IUPAC name Structure MS 103N-(cis-1-acetyl-2-(((cis-4- isopropyl(1,2,3,4,5,6-d6)cyclohexyl)oxy)methyl)piperidin- 3-yl)methanesulfonamide

381.2 104 cis-N-ethyl-2-(((cis-4- isopropyl(1,2,3,4,5,6-d6)cyclohexyl)oxy)methyl)-3- ((methylsulfonyl)amino)piperidine-1-carboxamide

410.3 105 cis-2-(((4-((tert- butyl(dimethyl)silyl)oxy)-cyclohexyl)oxy)methyl)-N-ethyl-3- ((methylsulfonyl)amino)piperidine-1-carboxamide

492.3 106 N-(cis-1-acetyl-2-(((cis-4- (trifluoromethyl)cyclohexyl)oxy)-methyl)piperidin-3- yl)methanesulfonamide

400.9 107 cis-N-ethyl-3- ((methylsulfonyl)amino)-2-(((cis-4-(trifluoromethyl)cyclohexyl)oxy)- methyl)piperidine-1-carboxamide

430 108 cis-2-(((4,4- difluorocyclohexyl)oxy)methyl)- N-ethyl-3-((methylsulfonyl)amino)piperidine- 1-carboxamide

398.1

TABLE 1-19 Ex. No. IUPAC name Structure MS 109N,N-dimethyl-N′-(cis-2-(((cis-4- phenylcyclohexyl)oxy)methyl)-piperidin-3-yl)sulfuric diamide

396.2 110 N-(cis-2-(((cis-4-(4- fluorophenyl)cyclohexyl)oxy)-methyl)piperidin-3- yl)methanesulfonamide

385 111 N′-(cis-1-acetyl-2-(((cis-4- phenylcyclohexyl)oxy)methyl)-piperidin-3-yl)-N,N- dimethylsulfuric diamide

438.1 112 N-(cis-1-acetyl-2-(((cis-4-(4- fluorophenyl)cyclohexyl)oxy)-methyl)piperidin-3- yl)methanesulfonamide

427.1 113 cis-N-ethyl-3- ((methylsulfonyl)amino)-2-(((cis-3-phenylcyclobutyl)oxy)methyl)- piperidine-1-carboxamide

410.1 114 N-(cis-1-acetyl-2-(((cis-3- phenylcyclobutyl)oxy)methyl)-piperidin-3-yl)methanesulfonamide

381

TABLE 1-20 Ex. No. IUPAC name Structure MS 115 N-(cis-2-(((cis-4-(2-fluorophenyl)cyclohexyl)oxy)- methyl)piperidin-3- yl)methanesulfonamide

385 116 N-(cis-1-acetyl-2-(((1- (pyridin-2-yl)piperidin-4-yl)oxy)methyl)piperidin-3- yl)methanesulfonamide

411.1 117 cis-N-ethyl-2-(((cis-4-(2- fluorophenyl)cyclohexyl)oxy)-methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxamide

456.1 118 cis-N-ethyl-3- ((methylsulfonyl)amino)-2-(((1-(pyrimidin-2-yl)piperidin-4- yl)oxy)methyl)piperidine-1- carboxamide

441.1 119 N-(cis-1-(methoxyacetyl)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

439.1 120 N-(cis-1-(oxetan-3-ylcarbonyl)- 2-(((cis-4-phenylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

451

TABLE 1-21 Ex. No. IUPAC name Structure MS 121 N-(cis-2-(((cis-4-phenylcyclohexyl)oxy)methyl)- 1-(tetrahydro-2H-pyran-4-ylcarbonyl)piperidin-3- yl)methanesulfonamide

479.1 122 N-(cis-2-(((cis-4- methylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

305.1 123 cis-N-ethyl-3- ((methylsulfonyl)amino)-2-(((1-phenylpiperidin-4- yl)oxy)methyl)piperidine- 1-carboxamide

439.1 124 N-(cis-2-(((cis-4-(1-methyl- 1H-pyrazol-4-yl)cyclohexyl)oxy)methyl)piperidin- 3-yl)methanesulfonamide

371.1 125 N-(cis-1-acetyl-2-(((4- methoxycyclohexyl)oxy)methyl)-piperidin-3-yl)methanesulfonamide

363.1 126 cis-N-ethyl-2-(((4- methoxycyclohexyl)oxy)methyl)-3-((methylsulfonyl)amino)piperidine- 1-carboxamide

392.1

TABLE 1-22 Ex. No. IUPAC name Structure MS 127 N-(cis-1-acetyl-2-(((4-(1H-pyrazol-1- yl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

399 128 N-(cis-1-acetyl-2-(((cis-4- methylcyclohexyl)oxy)methyl)-piperidin-3-yl)methanesulfonamide

347.1 129 cis-N-ethyl-2-(((cis-4- methylcyclohexyl)oxy)methyl)-3-((methylsulfonyl)amino)piperidine- 1-carboxamide

376.1 130 cis-N-ethyl-3- ((methylsulfonyl)amino)-2-(((trans-3-phenylcyclobutyl)oxy)methyl)- piperidine-1-carboxamide

410.1 131 N-(cis-1-acetyl-2-(((trans-3- phenylcyclobutyl)oxy)methyl)-piperidin-3-yl)methanesulfonamide

381.1 132 N-(cis-1-acetyl-2-(((cis-2- phenyl-1,3-dioxan-5-yl)oxy)methyl)piperidin-3- yl)methanesulfonamide

413.1

TABLE 1-23 Ex. No. IUPAC name Structure MS 133N-(cis-1-(N,N-dimethylglycyl)- 2-(((cis-4- phenylcyclohexyl)oxy)methyl)-piperidin-3-yl)methanesulfonamide

452.2 134 N-(cis-1-acetyl-2-(((cis-4-(1- methyl-1H-pyrazol-4-yl)cyclohexyl)oxy)methyl)piperidin- 3-yl)methanesulfonamide

413.1 135 N-(cis-2-(((cis-4-(3,4- difluorophenyl)cyclohexyl)oxy)-methyl)piperidin-3- yl)methanesulfonamide

403.2 136 cis-2-(((cis-4-(2,3- difluorophenyl)cyclohexyl)oxy)-methyl)-N-ethyl-3- ((methylsulfonyl)amino)piperidine- 1-carboxamide

474.1 137 cis-N-ethyl-2-(((cis-4- (1-methyl-1H-pyrazol-4-yl)cyclohexyl)oxy)methyl)-3- ((methylsulfonyl)amino)piperidine-1-carboxamide

442.1 138 N-(cis-2-(((cis-4- phenylcyclohexyl)oxy)methyl)-1-(1H-pyrazol-1-ylacetyl)piperidin- 3-yl)methanesulfonamide

475.1

TABLE 1-24 Ex. No. IUPAC name Structure MS 139N-(cis-1-(difluoroacetyl)-2-(((cis- 4-phenylcyclohexyl)oxy)methyl)-piperidin-3-yl)methanesulfonamide

443.2 140 cis-N-ethyl-3- ((methylsulfonyl)amino)-2-(((cis-2-phenyl-1,3-dioxan-5- yl)oxy)methyl)piperidine-1- carboxamide

442.1 141 N-(cis-1-acetyl-2-(((cis-4-(3,4-difluorophenyl)cyclohexyl)oxy)- methyl)piperidin-3-yl)methanesulfonamide

445.1 142 N-(cis-2-(((cis-4-(2,4- difluorophenyl)cyclohexyl)oxy)-methyl)piperidin-3- yl)methanesulfonamide

403 143 N-(cis-2-(((cis-4-(1-methyl- 1H-pyrazol-3-yl)cyclohexyl)oxy)methyl)piperidin- 3-yl)methanesulfonamide

369 144 cis-2-(((cis-4-(3,4- difluorophenyl)cyclohexyl)oxy)-methyl)-N-ethyl-3- ((methylsulfonyl)amino)piperidine- 1-carboxamide

474.1

TABLE 1-25 Ex. No. IUPAC name Structure MS 145N-(cis-1-acetyl-2-(((cis-4-(2,4- difluorophenyl)cyclohexyl)oxy)-methyl)piperidin-3- yl)methanesulfonamide

445.2 146 cis-2-(((cis-4-(2,4- difluorophenyl)cyclohexyl)oxy)-methyl)-N-ethyl-3- ((methylsulfonyl)amino)piperidine- 1-carboxamide

474.1 147 N-((2R,3S)-1-acetyl-2-(((cis-4-(3-fluorophenyl)cyclohexyl)oxy)- methyl)piperidin-3- yl)methanesulfonamide

427.2 148 (2R,3S)-N-ethyl-2-(((cis-4-(3- fluorophenyl)cyclohexyl)oxy)-methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxamide

456 149 N-(cis-2-(((cis-4- phenylcyclohexyl)oxy)methyl)-1-((3S)-tetrahydrofuran-3- ylcarbonyl)piperidin-3- yl)methanesulfonamide

465.1 150 N-(cis-2-(((cis-4- phenylcyclohexyl)oxy)methyl)-1-((3R)-tetrahydrofuran-3- ylcarbonyl)piperidin-3- yl)methanesulfonamide

465.1

TABLE 1-26 Ex. No. IUPAC name Structure MS 151 methyl cis-3-((methylsulfonyl)amino)-2-(((1- (pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)piperidine-1- carboxylate

428.1 152 N-(cis-1-(methylsulfonyl)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

443.1 153 N-(cis-1-acetyl-2-(((4- (cyclopropylmethoxy)cyclohexyl)-oxy)methyl)piperidin-3- yl)methanesulfonamide

403.2 154 methyl cis-2-(((cis-4-(1-methyl- 1H-pyrazol-3-yl)cyclohexyl)oxy)methyl)-3- ((methylsulfonyl)amino)piperidine-1-carboxylate

429.3 155 tert-butyl cis-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)- piperidine-1-carboxylate

465.2 156 N-methyl-N-(2-(cis-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)- piperidin-1-yl)-2- oxoethyl)acetamide

480.3

TABLE 1-27 Ex. No. IUPAC name Structure MS 157 N-(cis-2-(((cis-4-phenylcyclohexyl)oxy)methyl)-1- (1,3-thiazol-2-ylacetyl)piperidin-3-yl)methanesulfonamide

492.2 158 N-(cis-1-acetyl-2-(((cis-4-(1- methyl-1H-pyrazol-3-yl)cyclohexyl)oxy)methyl)piperidin- 3-yl)methanesulfonamide

413.2 159 cis-N-ethyl-2-(((cis-4-(1- methyl-1H-pyrazol-3-yl)cyclohexyl)oxy)methyl)-3- ((methylsulfonyl)amino)piperidine-1-carboxamide

442.2 160 methyl cis-2-(((1-(3- fluorophenyl)piperidin-4-yl)oxy)methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylate

444.2 161 methyl cis-2-(((1-(4- fluorophenyl)piperidin-4-yl)oxy)methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylate

444.2 162 methyl cis-2-(((1-(2- fluorophenyl)piperidin-4-yl)oxy)methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylate

444.2

TABLE 1-28 Ex. No. IUPAC name Structure MS 163 methyl cis-2-(((1-(3,5-difluorophenyl)piperidin-4- yl)oxy)methyl)-3-((methylsulfonyl)amino)piperidine- 1-carboxylate

462.2 164 methyl cis-2-(((1-(2- methoxyphenyl)piperidin-4-yl)oxy)methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylate

456.1 165 methyl cis-3- ((methylsulfonyl)amino)-2-(((1-(2-(trifluoromethyl)phenyl)piperidin- 4-yl)oxy)methyl)piperidine-1-carboxylate

494.2 166 methyl cis-2-(((1-(3- chlorophenyl)piperidin-4-yl)oxy)methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylate

460.3 167 methyl cis-2-(((1-(2- chlorophenyl)piperidin-4-yl)oxy)methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylate

460.2 168 methyl cis-3- ((methylsulfonyl)amino)-2-(((1-(pyridin-2-yl)piperidin-4- yl)oxy)methyl)piperidine-1- carboxylate

427.2

TABLE 1-29 Ex. No. IUPAC name Structure MS 169 methyl cis-3-((methylsulfonyl)amino)-2-(((1- (1,3-thiazol-2-yl)piperidin-4-yl)oxy)methyl)piperidine-1- carboxylate

433.1 170 methyl cis-3- ((methylsulfonyl)amino)-2-(((1-(1,3-thiazol-4-yl)piperidin-4- yl)oxy)methyl)piperidine-1- carboxylate

433.1 171 methyl cis-2-(((1-(4- methylpyrimidin-2-yl)piperidin-4-yl)oxy)methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylatehydrochloride

442.2 172 methyl cis-2-(((1-(5- methylpyrimidin-2-yl)piperidin-4-yl)oxy)methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylatehydrochloride

442.2 173 methyl cis-2-(((1-(4- methoxypyrimidin-2-yl)piperidin-4-yl)oxy)methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylatehydrochloride

458.2 174 methyl cis-3- ((methylsulfonyl)amino)-2-(((1-(pyrimidin-2-yl)pyrrolidin-3- yl)oxy)methyl)piperidine-1- carboxylate

414.2

TABLE 1-30 Ex. No. IUPAC name Structure MS 175 N-(cis-1-acetyl-2-(((4-(difluoromethyl)cyclohexyl)oxy)- methyl)piperidin-3-yl)methanesulfonamide

383.1 176 N-(cis-1-((1- hydroxycyclopropyl)carbonyl)-2- (((cis-4-phenylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

451.1 177 N-(cis-2-(((cis-4- phenylcyclohexyl)oxy)methyl)-1-pyruvoylpiperidin-3- yl)methanesulfonamide

435.1 178 methyl cis-2-(((4-methyl-1- (pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylatehydrochloride

442.2 179 cis-N-(cyanomethyl)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)- piperidine-1-carboxamide

447.1 180 N-((2R,3S)-1- (cyanoacetyl)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

432.1

TABLE 1-31 Ex. No. IUPAC name Structure MS 181 N-((2R,3S)-1-((methylsulfonyl)acetyl)-2-(((cis- 4-phenylcyclohexyl)oxy)methyl)-piperidin-3-yl)methanesulfonamide

485.1 182 N-((2R,3S)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)-1-propionylpiperidin-3- yl)methanesulfonamide

423.2 183 N-((2R,3S)-1-(((2R)-5- oxotetrahydrofuran-2-yl)carbonyl)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)-piperidin-3-yl)methanesulfonamide

479.2 184 N-((2R,3S)-1-(((2S)-5- oxotetrahydrofuran-2-yl)carbonyl)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)-piperidin-3-yl)methanesulfonamide

479.2 185 N-((2R,3S)-1-glycoloyl-2-(((cis-4-phenylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

425.1 186 methyl cis-2-(((1-(2,6- dichlorophenyl)piperidin-4-yl)oxy)methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylate

494

TABLE 1-32 Ex. No. IUPAC name Structure MS 187 N-((2R,3S)-1-((1-cyanocyclopropyl)carbonyl)-2- (((cis-4- phenylcyclohexyl)oxy)methyl)-piperidin-3-yl)methanesulfonamide

460.3 188 N-((2R,3S)-1-((2S)-2- hydroxypropanoyl)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

439.2 189 N-(cis-1-(2-hydroxy-2- methylpropanoyl)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

453.2 190 methyl cis-2-(((1-(3-chloropyridin-2-yl)piperidin-4-yl)oxy)methyl)-3- ((methylsulfonyl)amino)piperidine-1-carboxylate

461.2 191 methyl-d3 (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)- piperidine-l-carboxylate

428.3 192 cis-N-ethyl-2-(((cis-3-(4- methylphenyl)cyclobutyl)oxy)-methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxamide

424.2

TABLE 1-33 Ex. No. IUPAC name Structure MS 193N-(cis-1-(cyclopropylcarbonyl)-2- (((cis-3-phenylcyclobutyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

407.2 194 methyl cis-3- ((methylsulfonyl)amino)-2-(((cis-3-phenylcyclobutyl)oxy)methyl)- piperidine-1-carboxylate

395.1 195 cis-N-ethyl-2-(((1-(2- fluorophenyl)piperidin-4-yl)oxy)methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxamide

457.2 196 N-(cis-1-(cyclopropylcarbonyl)-2-(((1-(pyrimidin-2-yl)piperidin-4- yl)oxy)methyl)piperidin-3-yl)methanesulfonamide

438.2 197 N-(cis-1-(cyclopropylcarbonyl)-2- (((cis-4-methylcyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

371.2 198 N-(cis-1-acetyl-2-(((cis-4-(2,5-difluorophenyl)cyclohexyl)oxy)- methyl)piperidin-3-yl)methanesulfonamide

445.3

TABLE 1-34 Ex. No. IUPAC name Structure MS 199 methyl cis-3-((methylsulfonyl)amino)-2-(((1- phenylpiperidin-4-yl)oxy)methyl)piperidine-1- carboxylate

426.2 200 methyl (2R,3S)-2-(((cis-4-(3- fluorophenyl)cyclohexyl)oxy)-methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylate

441   201 N-(cis-2-(((1-(2- chlorophenyl)piperidin-4- yl)oxy)methyl)-1-(cyclopropylcarbonyl)piperidin-3- yl)methanesulfonamide

470.3 202 N-(cis-1-(cyclopropylcarbonyl)-2- (((1-(5-fluoropyrimidin-2-yl)piperidin-4- yl)oxy)methyl)piperidin-3- yl)methanesulfonamide

456.2 203 methyl cis-2-(((cis-3-(4- methylphenyl)cyclobutyl)oxy)-methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylate

409.1 204 N-(cis-1-acetyl-2-(((cis-4-(3- (trifluoromethyl)phenyl)-cyclohexyl)oxy)methyl)piperidin-3- yl)methanesulfonamide

477.2

TABLE 1-35 Ex. No. IUPAC name Structure MS 205 N-(cis-2-(((cis-4-(3-(trifluoromethyl)phenyl)- cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

435.2 206 N-(cis-1-acetyl-2-(((cis-3-(4- methylphenyl)cyclobutyl)oxy)-methyl)piperidin-3- yl)methanesulfonamide

395.3 207 cis-N-ethyl-3- ((methylsulfonyl)amino)-2-(((cis-4-(3-(trifluoromethyl)phenyl)- cyclohexyl)oxy)methyl)piperidine-1-carboxamide

506.2 208 N-(cis-1-(cyclohexylcarbonyl)-2-(((1-(pyrimidin-2-yl)piperidin-4- yl)oxy)methyl)piperidin-3-yl)methanesulfonamide

480.3 209 N-(cis-2-(((1-(2-chloro-3- fluorophenyl)piperidin-4-yl)oxy)methyl)-1- (cyclopropylcarbonyl)piperidin-3-yl)methanesulfonamide

488.1 210 N-(cis-1-((4,4- dimethylcyclohexyl)carbonyl)-2-(((1-(pyrimidin-2-yl)piperidin-4- yl)oxy)methyl)piperidin-3-yl)methanesulfonamide

508.3

TABLE 1-36 Ex. No. IUPAC name Structure MS 211N-(cis-1-(cyclopropylcarbonyl)-2- (((3,3-difluoro-1-(pyrimidin-2-yl)piperidin-4- yl)oxy)methyl)piperidin-3- yl)methanesulfonamide

474.2 212 N-(cis-2-(((1-(2-chloro-5- fluorophenyl)piperidin-4-yl)oxy)methyl)-1- (cyclopropylcarbonyl)piperidin-3-yl)methanesulfonamide

488.1 213 N-((2R,3S)-1-(cyclopropylcarbonyl)- 2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)- methyl)piperidin-3-yl)methanesulfonamide

471.2 214 N-((2R,3S)-1-(cyclopropylcarbonyl)- 2-(((cis-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl) piperidin-3-yl)methanesulfonamide

471.2 215 methyl (2R,3S)-2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)- methyl)-3-((methylsulfonyl)amino)piperidine- 1-carboxylate

461.3 216 N-(cis-1-acetyl-2-(((4-fluoro-4-(3-fluorophenyl)cyclohexyl)oxy)- methyl)piperidin-3- yl)methanesulfonamide

445.2

TABLE 1-37 Ex. No. IUPAC name Structure MS 217N-((2R,3S)-1-acetyl-2-(((cis-4- (2,5- difluorophenyl)cyclohexyl)oxy)-methyl)piperidin-3- yl)methanesulfonamide

445.2 218 N-(cis-2-(((1-(2- fluorophenyl)piperidin-4- yl)oxy)methyl)-1-glycoloylpiperidin-3- yl)methanesulfonamide

444.2 219 N-(cis-2-(((1-(2- fluorophenyl)piperidin-4- yl)oxy)methyl)-1-propionylpiperidin-3- yl)methanesulfonamide

442.2 220 N-(cis-1-((1- fluorocyclopropyl)carbonyl)-2-(((1-(2-fluorophenyl)piperidin-4- yl)oxy)methyl)piperidin-3-yl)methanesulfonamide

472.2 221 N-(cis-1-(((1S,2S)-2- fluorocyclopropyl)carbonyl)-2-(((1-(2-fluorophenyl)piperidin-4- yl)oxy)methyl)piperidin-3-yl)methanesulfonamide

472.2 222 N-(cis-1-(((1R,2S)-2- fluorocyclopropyl)carbonyl)-2-(((1-(2-fluorophenyl)piperidin-4- yl)oxy)methyl)piperidin-3-yl)methanesulfonamide

472.2

TABLE 1-38 Ex. No. IUPAC name Structure MS 223N-(cis-1-(cyclobutylcarbonyl)-2- (((1-(2-fluorophenyl)piperidin-4-yl)oxy)methyl)piperidin-3- yl)methanesulfonamide

468.2 224 N-(cis-2-(((1-(2- fluorophenyl)piperidin-4- yl)oxy)methyl)-1-isobutyrylpiperidin-3- yl)methanesulfonamide

456.3 225 N-(cis-1-((2,2- difluorocyclopropyl)carbonyl)-2-(((1-(2-fluorophenyl)piperidin-4- yl)oxy)methyl)piperidin-3-yl)methanesulfonamide

490.2 226 N-(cis-1-(cyclopropylacetyl)-2-(((1-(2-fluorophenyl)piperidin-4- yl)oxy)methyl)piperidin-3-yl)methanesulfonamide

468.2 227 N-(cis-1-butyryl-2-(((1-(2- fluorophenyl)piperidin-4-yl)oxy)methyl)piperidin-3- yl)methanesulfonamide

456.2 228 ethyl cis-2-(((1-(2- fluorophenyl)piperidin-4-yl)oxy)methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylate

458.2

TABLE 1-39 Ex. No. IUPAC name Structure MS 229N-(cis-1-(cyclopentylcarbonyl)-2- (((1-(2-fluorophenyl)piperidin-4-yl)oxy)methyl)piperidin-3- yl)methanesulfonamide

482.2 230 N-(cis-2-(((1-(2- fluorophenyl)piperidin-4-yl)oxy)methyl)-1-(3- methylbutanoyl)piperidin-3- yl)methanesulfonamide

470.2 231 N-(cis-2-(((1-(2- fluorophenyl)piperidin-4-yl)oxy)methyl)-1-(tetrahydro-2H- pyran-4-ylcarbonyl)piperidin-3-yl)methanesulfonamide

498.2 232 N-(cis-2-(((1-(2- fluorophenyl)piperidin-4-yl)oxy)methyl)-1-(3- hydroxypropanoyl)piperidin-3- yl)methanesulfonamide

458.2 233 N-(cis-2-(((1-(2- fluorophenyl)piperidin-4-yl)oxy)methyl)-1-((3- oxocyclobutyl)carbonyl)piperidin-3-yl)methanesulfonamide

482.2 234 N-(cis-1-(3,3-dimethylbutanoyl)-2-(((1-(2-fluorophenyl)piperidin-4- yl)oxy)methyl)piperidin-3-yl)methanesulfonamide

484.3

TABLE 1-40 Ex. No. IUPAC name Structure MS 235 N-(cis-2-(((1-(2-fluorophenyl)piperidin-4- yl)oxy)methyl)-1-(oxetan-3-ylcarbonyl)piperidin-3- yl)methanesulfonamide

470.2 236 N-(cis-1-(cyclohexylcarbonyl)-2-(((1-(2-fluorophenyl)piperidin-4- yl)oxy)methyl)piperidin-3-yl)methanesulfonamide

496.3 237 isopropyl cis-2-(((1-(2- fluorophenyl)piperidin-4-yl)oxy)methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylate

472.2 238 N-(cis-1-((4,4- difluorocyclohexyl)carbonyl)-2-(((1-(2-fluorophenyl)piperidin-4- yl)oxy)methyl)piperidin-3-yl)methanesulfonamide

532.3 239 N-((2R,3S)-2-(((cis-4-(2,3,5- trifluorophenyl)cyclohexyl)oxy)-methyl)piperidin-3- yl)methanesulfonamide

421.2 240 N-((2R,3S)-1-acetyl-2-(((cis-4-(2-fluorophenyl)cclohexyl)oxy)- methyl)piperidin-3- yl)methanesulfonamide

427.1

TABLE 1-41 Ex. No. IUPAC name Structure MS 241 methyl(2R,3S)-2-(((cis-4-(3,5- difluorophenyl)cyclohexyl)oxy)- methyl)-3-((methylsulfonyl)amino)piperidine- 1-carboxylate

459.1 242 N-((2R,3S)-1-(cyclopropylcarbonyl)- 2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)- methyl)piperidin-3-yl)methanesulfonamide

469.1 243 N-((2R,3S)-1-acetyl-2-(((cis-4- (2,3,5-trifluorophenyl)cyclohexyl)oxy)- methyl)piperidin-3-yl)methanesulfonamide

463.1 244 methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4- (2,3,5-trifluorophenyl)cyclohexyl)oxy)- methyl)piperidine-1-carboxylate

477.1 245 N-((2R,3S)-1-(cyclopropylcarbonyl)- 2-(((cis-4-(2,3,5-trifluorophenyl)cyclohexyl)oxy)- methyl)piperidin-3-yl)methanesulfonamide

489.1 246 N-((2R,3S)-1-(cyclopropylcarbonyl)-2-(((1-(2-fluorophenyl)piperidin-4- yl)oxy)methyl)piperidin-3-yl)methanesulfonamide

454.2

TABLE 1-42 Ex. No. IUPAC name Structure MS 247N-(cis-1-(cyclopropylcarbonyl)-2- (((1-phenylpiperidin-4-yl)oxy)methyl)piperidin-3- yl)methanesulfonamide

436.2 248 cis-N-ethyl-3- ((methylsulfonyl)amino)-2-(((cis-3-(4-(trifluoromethyl)phenyl)- cyclobutyl)oxy)methyl)piperidine-1-carboxamide

478.2 249 cis-N-ethyl-3- ((methylsulfonyl)amino)-2-(((cis-4-(2-(trifluoromethyl)phenyl)- cyclohexyl)oxy)methyl)piperidine-1-carboxamide

506.2 250 N-((2R,3S)-1-(cyclopropylcarbonyl)- 2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)- methyl)piperidin-3-yl)methanesulfonamide

471.2 251 N-(cis-1-(cyclopropylcarbonyl)-2- (((4-(pyridin-2-yl)cyclohexyl)oxy)methyl)piperidin- 3-yl)methanesulfonamide

436.2 252 N-(cis-1-acetyl-2-(((cis-4-(3-cyanophenyl)cyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

434.1

TABLE 1-43 Ex. No. IUPAC name Structure MS 253 N-(cis-2-(((cis-4-(3-cyanophenyl)cyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

392.2 254 cis-2-(((cis-4-(3- cyanophenyl)cyclohexyl)oxy)methyl)-N-ethyl-3- ((methylsulfonyl)amino)piperidine- 1-carboxamide

463.2 255 isopropyl cis-3- ((methylsulfonyl)amino)-2-(((1-(pyrimidin-2-yl)piperidin-4- yl)oxy)methyl)piperidine-1- carboxylate

456.2 256 isopropyl cis-3- ((methylsulfonyl)amino)-2-(((1-(quinazolin-2-yl)piperidin-4- yl)oxy)methyl)piperidine-1- carboxylate

506.2 257 methyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4- (2,3,6-trifluorophenyl)cyclohexyl)oxy)- methyl)piperidine-1-carboxylate

477.1 258 N-((2R,3S)-1-(cyclopropylcarbonyl)- 2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)- methyl)piperidin-3-yl)methanesulfonamide

489.1

TABLE 1-44 Ex. No. IUPAC name Structure MS 259 isopropylcis-2-(((1-(1,3- benzothiazol-2-yl)piperidin-4- yl)oxy)methyl)-3-((methylsulfonyl)amino)piperidine- 1-carboxylate

511.2 260 N-((2R,3S)-2-(((cis-4-(2- fluorophenyl)cyclohexyl)oxy)-methyl)piperidin-3- yl)methanesulfonamide

385.1 261 isopropyl cis-2-(((1-(isoquinolin-1-yl)piperidin-4-yl)oxy)methyl)-3- ((methylsulfonyl)amino)piperidine-1-carboxylate

505.2 262 N-(cis-2-(((cis-4-(2- cyanophenyl)cyclohexyl)oxy)methyl)-piperidin-3-yl)methanesulfonamide

392.2 263 cis-2-(((cis-4-(2- cyanophenyl)cyclohexyl)oxy)methyl)-N-ethyl-3- ((methylsulfonyl)amino)piperidine- 1-carboxamide

463.1 264 isopropyl (2R,3S)-2-(((cis-4-(3- fluorophenyl)cyclohexyl)oxy)-methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylate

471.2

TABLE 1-45 Ex. No. IUPAC name Structure MS 265 methyl cis-2-(((cis-4-(2-cyanophenyl)cyclohexyl)oxy)methyl)- 3-((methylsulfonyl)amino)piperidine- 1-carboxylate

450.1 266 cis-2-(((cis-3- benzylcyclobutyl)oxy)methyl)-N- ethyl-3-((methylsulfonyl)amino)piperidine- 1-carboxamide

424.2 267 methyl (2R,3S)-2-(((cis-4-(2- fluorophenyl)cyclohexyl)oxy)-methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylate

443.3 268 N-((2R,3S)-1-(cyclopropylcarbonyl)- 2-(((cis-4-(2-fluorophenyl)cyclohexyl)oxy)- methyl)piperidin-3- yl)methanesulfonamide

453.2 269 N-(cis-2-(((cis-4-(3- methoxyphenyl)cyclohexyl)oxy)-methyl)piperidin-3- yl)methanesulfonamide

397.2 270 methyl cis-2-(((cis-4-(3- methoxyphenyl)cyclohexyl)oxy)-methyl)-3- ((methylsulfonyl)amino)piperidine 1-carboxylate

455.2

TABLE 1-46 Ex. No. IUPAC name Structure MS 271N-(cis-1-acetyl-2-(((cis-4-(3- methoxyphenyl)cyclohexyl)oxy)-methyl)piperidin-3- yl)methanesulfonamide

439.2 272 cyclopropyl (2R,3S)-2-(((cis-4-(3-fluorophenyl)cyclohexyl)oxy)- methyl)-3-((methylsulfonyl)amino)piperidine- 1-carboxylate

469.2 273 methyl cis-3- ((methylsulfonyl)amino)-2-(((3-phenoxycyclopentyl)oxy)methyl)- piperidine-1-carboxylate

427.1 274 methyl cis-3- ((methylsulfonyl)amino)-2-(((1r,4′r)-3H-spiro[2-benzofuran- 1,1′-cyclohexan]-4′-yloxy)methyl)piperidine-1- carboxylate

453.1 275 methyl cis-3- ((methylsulfonyl)amino)-2-(((1s,4′s)-3H-spiro[2-benzofuran- 1,1′-cyclohexan]-4′-yloxy)methyl)piperidine-1- carboxylate

453.1 276 2,2,2-trifluoroethyl (2R,3S)-2- (((cis-4-(3-fluorophenyl)cyclohexyl)oxy)- methyl)-3-((methylsulfonyl)amino)piperidine- 1-carboxylate

509.2

TABLE 1-47 Ex. No. IUPAC name Structure MS 277 methyl(2R,3S)-2-(((cis-4-(2- methoxyphenyl)cyclohexyl)oxy)- methyl)-3-((methylsulfonyl)amino)piperidine- 1-carboxylate

455.2 278 N-(cis-1-acetyl-2-(((cis-4-(2-cyanophenyl)cyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

434.1 279 N-(cis-1-(cyclopropylcarbonyl)-2- (((cis-4-phenylcyclohexyl)oxy)methyl)- piperidin-3-yl)ethanesulfonamide

449.2 280 methyl cis-3- ((methylsulfonyl)amino)-2-(((trans-3-phenoxycyclobutyl)oxy)methyl)- piperidine-1-carboxylate

411.1 281 cis-N-ethyl-3- ((methylsulfonyl)amino)-2-(((trans-3-phenoxycyclobutyl)oxy)methyl)- piperidine-1-carboxamide

426.1 282 (2R,3S)-N-ethyl-3- ((methylsulfonyl)amino)-2-(((cis-4-(2-(trifluoromethyl)phenyl)- cyclohexyl)oxy)methyl)piperidine-1-carboxamide

506.2

TABLE 1-48 Ex. No. IUPAC name Structure MS 283N-((2R,3S)-1-glycoloyl-2-(((cis-4- (2-(trifluoromethyl)phenyl)-cyclohexyl)oxy)methyl)piperidin-3- yl)methanesulfonamide

493.2 284 1-methylcyclopropyl cis-3- ((methylsulfonyl)amino)-2-(((1-(pyrimidin-2-yl)piperidin-4- yl)oxy)methyl)piperidine-1- carboxylate

468.2 285 cis-2-(((trans-3- benzylcyclobutyl)oxy)methyl)-N- ethyl-3-((methylsulfonyl)amino)piperidine- 1-carboxamide

424.2 286 2,2,2-trifluoroethyl cis-3- ((methylsulfonyl)amino)-2-(((1-(pyrimidin-2-yl)piperidin-4- yl)oxy)methyl)piperidine-1- carboxylate

496.1 287 cyclopropyl cis-3- ((methylsulfonyl)amino)-2-(((1-(pyrimidin-2-yl)piperidin-4- yl)oxy)methyl)piperidine-1- carboxylate

454.2 288 2,2,2-trifluoroethyl cis-2-(((1-(2- fluorophenyl)piperidin-4-yl)oxy)methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylate

512.2

TABLE 1-49 Ex. No. IUPAC name Structure MS 289 2,2,2-trifluoroethylcis-3- ((methylsulfonyl)amino)-2-(((1- phenylpiperidin-4-yl)oxy)methyl)piperidine-1- carboxylate

494.2 290 cyclopropyl cis-2-(((1-(2- fluorophenyl)piperidin-4-yl)oxy)methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylate

470.2 291 N-((2R,3S)-1-acetyl-2-(((cis-4-(2-methoxyphenyl)cyclohexyl)oxy)- methyl)piperidin-3- yl)methanesulfonamide

439.2 292 N-(cis-2-(((cis-4-(2- (trifluoromethoxy)phenyl)-cyclohexyl)oxy)methyl)piperidin-3- yl)methanesulfonamide

451.1 293 N-(cis-1-acetyl-2-(((cis-4-(2- (trifluoromethoxy)phenyl)-cyclohexyl)oxy)methyl)piperidin-3- yl)methanesulfonamide

493.2 294 N-(cis-1-(cyclopropylcarbonyl)-2- (((cis-4-(2-(trifluoromethoxy)phenyl)- cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

519.2

TABLE 1-50 Ex. No. IUPAC name Structure MS 295 cis-N-ethyl-3-((methylsulfonyl)amino)-2-(((cis-4- (2-(trifluoromethoxy)phenyl)-cyclohexyl)oxy)methyl)piperidine-1- carboxamide

522.2 296 N-(cis-2-(((cis-4-(3- (trifluoromethoxy)phenyl)-cyclohexyl)oxy)methyl)piperidin-3- yl)methanesulfonamide

451.1 297 N-(cis-1-acetyl-2-(((cis-4-(3- (trifluoromethoxy)phenyl)cyclo-hexyl)oxy)methyl)piperidin-3- yl)methanesulfonamide

493.2 298 methyl cis-3- ((methylsulfonyl)amino)-2-(((cis-4-(3-(trifluoromethoxy)phenyl)- cyclohexyl)oxy)methyl)piperidine-1-carboxylate

507.2 299 N-(cis-1-(cyclopropylcarbonyl)-2- (((cis-4-(3-(trifluoromethoxy)phenyl)- cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

519.1 300 cis-N-ethyl-3- ((methylsulfonyl)amino)-2-(((cis-4-(3-(trifluoromethoxy)phenyl)- cyclohexyl)oxy)methyl)piperidine-1-carboxamide

522.2

TABLE 1-51 Ex. No. IUPAC name Structure MS 301 methyl cis-3-((ethylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)-piperidine-1-carboxylate

439.2 302 methyl cis-3- ((methylsulfonyl)amino)-2-(((3-phenoxycyclopentyl)oxy)methyl)- piperidine-1-carboxylate

427.2 303 ethyl (2R,3S)-3- ((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)- piperidine-1-carboxylate

439.2 304 N-((2R,3S)-1-(cyclopropylcarbonyl)- 2-(((cis-4-(3-methoxyphenyl)cyclohexyl)oxy)- methyl)piperidin-3- yl)methanesulfonamide

465.2 305 2,2,2-trifluoroethyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((1- (pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)piperidine-1- carboxylate

496.2 306 N-((2R,3S)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)-1- (3,3,3-trifluoropropanoyl)piperidin-3- yl)methanesulfonamide

477.2

TABLE 1-52 Ex. No. IUPAC name Structure MS 307 isopropyl cis-3-((methylsulfonyl)amino)-2-(((cis-3- phenylcyclobutyl)oxy)methyl)-piperidine-1-carboxylate

425.2 308 N-(cis-1-(cyclopropylacetyl)-2- (((cis-3-phenylcyclobutyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

421.2 309 methyl (2R,3S)-3- ((dimethylsulfamoyl)amino)-2- (((cis-4-phenylcyclohexyl)oxy)methyl)- piperidine-1-carboxylate

454.2 310 N′-((2R,3S)-1- (cyclopropylcarbonyl)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)- piperidin-3-yl)-N,N- dimethylsulfuricdiamide

464.2 311 N-(cis-2-(((cis-4-(2- ethylphenyl)cyclohexyl)oxy)methyl)-piperidin-3-yl)methanesulfonamide

395.3 312 N-((2R,3S)-1-acetyl-2-(((cis-4-(2-ethylphenyl)cyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

437.2

TABLE 1-53 Ex. No. IUPAC name Structure MS 3131,1,1-trifluoropropan-2-yl cis-3- ((methylsulfonyl)amino)-2-(((1-(pyrimidin-2-yl)piperidin-4- yl)oxy)methyl)piperidine-1- carboxylate

510.1 314 1,1,1,3,3,3-hexafluoropropan-2-ylcis-3-((methylsulfonyl)amino)-2- (((1-(pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)piperidine-1- carboxylate

564.1 315 2,2,2-trifluoroethyl cis-3- ((dimethylsulfamoyl)amino)-2-(((1-(pyrimidin-2-yl)piperidin-4- yl)oxy)methyl)piperidine-1- carboxylate

525.2 316 1,1,1-trifluoropropan-2-yl cis-3-((dimethylsulfamoyl)amino)-2-(((1- (pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)piperidine-1- carboxylate

539.2 317 cis-N-ethyl-3- ((methylsulfonyl)amino)-2-(((cis-3-phenoxycyclobutyl)oxy)methyl)- piperidine-1-carboxamide

426.1 318 N-((2R,3S)-2-(((cis-4-(2- methylphenyl)cyclohexyl)oxy)-methyl)piperidin-3- yl)methanesulfonamide

381.2

TABLE 1-54 Ex. No. IUPAC name Structure MS 319N-((2R,3S)-1-acetyl-2-(((cis-4-(2- methylphenyl)cyclohexyl)oxy)-methyl)piperidin-3- yl)methanesulfonamide

423.2 320 N-((2R,3S)-2-(((cis-4-(2- (difluoromethyl)phenyl)cyclohexyl)-oxy)methyl)piperidin-3- yl)methanesulfonamide

417.1 321 N-(cis-1-acetyl-2-(((cis-4-(2,6-dimethylphenyl)cyclohexyl)oxy)- methyl)piperidin-3-yl)methanesulfonamide

437.2 322 methyl cis-2-(((cis-4-(2- (difluoromethyl)phenyl)cyclohexyl)-oxy)methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylate

473.1 323 N-((2R,3S)-1-acetyl-2-(((cis-4-(2-(difluoromethyl)phenyl)cyclohexyl)- oxy)methyl)piperidin-3-yl)methanesulfonamide

459.2 324 methyl (2R,3S)-2-(((cis-4-(2-(difluoromethyl)phenyl)cyclohexyl)- oxy)methyl)-3-((methylsulfonyl)amino)piperidine- 1-carboxylate

473.1

TABLE 1-55 Ex. No. IUPAC name Structure MS 325N-(cis-2-(((4-(3,5-difluorophenyl)- 4-fluorocyclohexyl)oxy)methyl)-piperidin-3-yl)methanesulfonamide

421.2 326 N-(cis-2-(((cis-4-(pyrimidin-2-yl)cyclohexyl)oxy)methyl)piperidin- 3-yl)methanesulfonamide

369.1 327 N-(cis-1-(cyclopropylcarbonyl)-2- (((4-(3,5-difluorophenyl)-4-fluorocyclohexyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

489.2 328 N-(cis-1-(cyclopropylcarbonyl)-2- (((cis-4-(pyrimidin-2-yl)cyclohexyl)oxy)methyl)piperidin- 3-yl)methanesulfonamide

437.2 329 isopropyl cis-2-(((cis-2-methyl-1-(pyrimidin-2-yl)piperidin-4- yl)oxy)methyl)-3-((methylsulfonyl)amino)piperidine- 1-carboxylate

470.2 330 isopropyl cis-2-(((trans-2-methyl-1-(pyrimidin-2-yl)piperidin-4- yl)oxy)methyl)-3-((methylsulfonyl)amino)piperidine- 1-carboxylate

470.2

TABLE 1-56 Ex. No. IUPAC name Structure MS 331 methylcis-2-(((trans-4-hydroxy-4- phenylcyclohexyl)oxy)methyl)-3-((methylsulfonyl)amino)piperidine- 1-carboxylate

439.1 332 N-(cis-2-(((cis-4-(2- chlorophenyl)cyclohexyl)oxy)-methyl)piperidin-3- yl)methanesulfonamide

401.1 333 N-((2R,3S)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)-piperidin-3-yl)methanesulfonamide (s)-mandelate

367.2 334 N-(cis-1-acetyl-2-(((cis-4-(2- chlorophenyl)cyclohexyl)oxy)-methyl)piperidin-3- yl)methanesulfonamide

443.2 335 methyl cis-2-(((cis-4-(2- chlorophenyl)cyclohexyl)oxy)-methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylate

459.2 336 N-(cis-2-(((3- phenylcyclopentyl)oxy)methyl)-piperidin-3-yl)methanesulfonamide

353.2

TABLE 1-57 Ex. No. IUPAC name Structure MS 337 N-(cis-1-acetyl-2-(((3-phenylcyclopentyl)oxy)methyl)- piperidin-3-yl)methanesulfonamide

395.3 338 methyl cis-3- ((methylsulfonyl)amino)-2-(((3-phenylcyclopentyl)oxy)methyl)- piperidine-1-carboxylate

411.2 339 cis-N-ethyl-3- ((methylsulfonyl)amino)-2-(((3-phenylcyclopentyl)oxy)methyl)- piperidine-1-carboxamide

424.1 340 N-((2R,3S)-1-glycoloyl-2-(((cis-4- (2,3,6-trifluorophenyl)cyclohexyl)oxy)- methyl)piperidin-3-yl)methanesulfonamide

479.2 341 isopropyl cis-2-(((trans-3-fluoro-1-(pyrimidin-2-yl)piperidin-4- yl)oxy)methyl)-3-((methylsulfonyl)amino)piperidine- 1-carboxylate

474.2 342 isopropyl cis-2-(((cis-3-fluoro-1-(pyrimidin-2-yl)piperidin-4- yl)oxy)methyl)-3-((methylsulfonyl)amino)piperidine- 1-carboxylate

474.2

TABLE 1-58 Ex. No. IUPAC name Structure MS 343 methyl cis-2-(((cis-4-(3-hydroxyphenyl)cyclohexyl)oxy)- methyl)-3-((methylsulfonyl)amino)piperidine- 1-carboxylate

441.2 344 methyl cis-2-(((cis-4-(4- methoxyphenyl)cyclohexyl)oxy)-methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylate

455.2 345 methyl cis-2-(((cis-4-(4- hydroxyphenyl)cyclohexyl)oxy)-methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylate

439.0 346 methyl cis-2-(((4-hydroxy-4-(2- methoxyphenyl)cyclohexyl)oxy)-methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylate

469.1 347 methyl cis-2-(((cis-4-(2- hydroxyphenyl)cyclohexyl)oxy)-methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylate

439.2 348 methyl (2R,3S)-2-(((cis-4-(4- hydroxyphenyl)cyclohexyl)oxy)-methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxylate

439.1

TABLE 1-59 Ex. No. ICIPAC name Structure MS 349 methyl cis-2-((1,4-dioxaspiro[4.5]dec-8-yloxy)methyl)- 3-((methylsulfonyl)amino)piperidine-1-carboxylate

405.1 350 cis-N-ethyl-3- ((methylsulfonyl)amino)-2- ((((1S,2S)-2-phenoxycyclopentyl)oxy)methyl)- piperidine-1-carboxamide

438.0 351 cis-2-((((3S)-1-benzoylpyrrolidin- 3-yl)oxy)methyl)-N-ethyl-3-((methylsulfonyl)amino)piperidine- 1-carboxamide

453.3 352 cis-2-((((3R)-1-benzoylpyrrolidin- 3-yl)oxy)methyl)-N-ethyl-3-((methylsulfonyl)amino)piperidine- 1-carboxamide

451.0 353 N-(cis-2-(((cis-4- phenylcyclohexyl)oxy)methyl)- piperidin-3-yl)cyclopropanesulfonamide

393.2 354 N-(cis-1-acetyl-2-(((cis-4- phenylcyclohexyl)oxy)methyl)-piperidin-3- yl)cyclopropanesulfonamide

435.1

TABLE 1-60 Ex. No. IUPAC name Structure MS 355cis-3-((cyclopropylsulfonyl)amino)- N-ethyl-2-(((cis-4-phenylcyclohexyl)oxy)methyl)- piperidine-1-carboxamide

464.1 356 isopropyl cis-3- ((cyclopropylsulfonyl)amino)-2-(((1-(pyrimidin-2-yl)piperidin-4- yl)oxy)methyl)piperidine-1-carboxylate

482.2 357 N-(cis-1-acetyl-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-piperidin-3- yl)cyclopropanesulfonamide

401.1 358 N-(cis-1-acetyl-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-piperidin-3- yl)cyclohexanesulfonamide

443.2 359 cis-3-((cyclopropylsulfonyl)amino)- N-methyl-2-(((cis-4-phenylcyclohexyl)oxy)methyl)- piperidine-1-carboxamide

450.1 360 2,2,2-trifluoroethyl cis-3- ((cyclopropylsulfonyl)amino)-2-(((1-(pyrimidin-2-yl)piperidin-4- yl)oxy)methyl)piperidine-1-carboxylate

522.2

TABLE 1-61 Ex. No. IUPAC name Structure MS 3611,1,1,3,3,3-hexafluoropropan-2-yl cis-3-((cyclopropylsulfonyl)amino)-2-(((1-(pyrimidin-2-yl)piperidin-4- yl)oxy)methyl)piperidine-1-carboxylate

590.2 362 1,1,1-trifluoropropan-2-yl cis-3-((cyclopropylsulfonyl)amino)-2- (((1-(pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)piperidine-1- carboxylate

536.3 363 N-(1-acetyl-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-(2,3,4,5,6-d5)piperidin-3- yl)methanesulfonamide

380.2 364 ethyl 3-((ethylsulfonyl)amino)-2- (((cis-4-isopropylcyclohexyl)oxy)methyl)- piperidine-1-carboxylate

417.2 365 ethyl 3-((ethylsulfonyl)amino)-2- (((cis-4-methylcyclohexyl)oxy)methyl)- piperidine-1-carboxylate

391.2 366 N-(1-acetyl-2-(((cis-4-tert- butylcyclohexyl)oxy)methyl)-piperidin-3-yl)ethanesulfonamide

403.1

TABLE 1-62 Ex. No. IUPAC name Structure MS 367 N-(2-(((cis-4-isopropyl-cyclohexyl)oxy)methyl)-1- (tetrahydrofuran-3- ylcarbonyl)piperidin-3-yl)methanesulfonamide

431.2 368 N-(2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-1-(oxetan-3-ylcarbonyl)piperidin-3- yl)methanesulfonamide

417.1 369 N-ethyl-2-(((cis-4- isopropylcyclohexyl)oxy)methyl)-3-((methylsulfonyl)amino)piperidine- 1-carboxamide

404.2 370 N-ethyl-3-((methylsulfonyl)amino)- 2-(((cis-4-phenylcyclohexyl)oxy)methyl)- piperidine-1-carboxamide

438.2 371 trans-N-ethyl-2-(((cis-4-(3- fluorophenyl)cyclohexyl)oxy)-methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxamide

456.0 372 trans-N-ethyl-2-(((cis-4-(2- fluorophenyl)cyclohexyl)oxy)-methyl)-3- ((methylsulfonyl)amino)piperidine- 1-carboxamide

456.1

Experimental Example 1 Obtainment of Cell Stably Expressing Human OrexinType 2 Receptor

To obtain a cell clone stably expressing human orexin type 2 receptor,human orexin type 2 receptor cDNA was inserted into pcDNA3.1(+) plasmidvector (Invitrogen), and a plasmid DNA for expression of human orexintype 2 receptor (pcDNA3.1(+)/hOX2R) was cloned. The plasmid DNA wasintroduced into CHO-dhfr cell by an electroporation method, and humanorexin type 2 receptor expressing clone cells were obtained by limitingdilution method by using G418 drug resistance as a selection marker.

Experimental Example 2-1 Measurement of Orexin Type 2 Receptor AgonistActivity

Chinese hamster ovary (CHO) dhfr-cells forcibly expressing human orexintype 2 receptor (hOX2R) were seeded in each well of Black clear bottomplate (384 wells) (Becton, Dickinson and Company) by 10,000 cells, andcultured for 16 hr in an MEM-alpha (Nikken-Bio Co., Ltd.) mediumcontaining 100 U/ml penicillin, 100 μg/ml streptomycin, 0.5 g/ml G418(all above Invitrogen), and 10% fetal calf serum (Thermo), under theconditions of 37° C., 5% CO₂. After removal of the medium, 30 μL ofassay buffer 1 (0.1% bovine serum albumin (Wako Pure ChemicalIndustries, Ltd.), 1.25 mM probenecid, 10% B2-Quencher, 2.5 μg/mLFluo-4AM, 10 mM HEPES (DOJINDO)) was added, and the cells were incubatedfor 60 min under the conditions of 37° C., 5% CO₂. A test compound wasdissolved in dimethyl sulfoxide to 10 mM, and then diluted with assaybuffer 2 (20 mM HEPES, Hanks' balanced salt solution (Invitrogen), 0.1%bovine serum albumin). For the reaction, a test compound solution (10μL) was added using Fluorescent Imaging Plate Reader TETRA (FLIPR TETRA;manufactured by Molecular Devices), a fluorescence value (excitationwavelength 488 nm, measurement wavelength 570 nm) of each well wasmeasured every one second for 1 min, and the agonist activity wasdetermined using the area of the fluorescence value as an indicator ofintracellular Ca²⁺ concentration. The agonist activity of the testcompound was calculated assuming that the fluorescence value of the welladded with only the dilution buffer was 0% and the fluorescence value ofthe well added with 10 nM human orexin B (PEPTIDE INSTITUTE, INC.)buffer was 100%. The agonist activity values EC₅₀ and Emax of eachcompound are shown below. As used herein, Emax indicates the value at 30uM concentration when orexin B is converted to a full agonist (maximumvalue of agonist activity: 100%). As is clear from the results, thecompound of the present invention was shown to have an agonist activityon hOX2R.

TABLE 2-1 Ex. No. EC₅₀ (nM) Emax (%) 2 1.9 99 3 540 96 4 44 106 5 2.2 987 250 100 8 5.6 96 10 220 113 11 2.0 114 13 130 115 14 6.6 105 15 280105 16 0.84 99 18 520 96 19 12 102 20 3.4 100 21 200 108 22 5.3 98 231200 90 24 21 102 25 7.9 94 27 310 108 28 2.7 96 29 17 104 30 0.11 11331 0.66 95 32 15 102 33 68 98 35 93 99 36 880 74 37 880 97 39 940 93 40720 91 42 210 97 43 1100 93 44 1300 96 45 330 100 47 60 101 53 980 96 544100 88 55 140 97 60 140 101 62 2300 93 65 1300 95 66 3800 87 67 910 9370 97 98 71 4300 83 72 89 96 73 560 92 74 750 89 75 220 88 76 300 103 771000 91 78 63 91 79 330 85 80 660 98 84 840 98 87 4900 82 90 2800 74 9139 89 92 370 92 93 2300 84 95 4300 89 96 26 95 97 4.5 108 98 2.9 107 9913 112 100 2.2 112 101 2.3 115 102 1.2 101 103 170 98 104 2.2 100 1064800 89 107 120 75 109 480 102 111 13 97 112 420 94 113 59 93 114 350079 115 770 97 117 0.12 91 118 4.6 105 119 30 107 120 61 96

TABLE 2-2 Ex. No. EC₅₀ (nM) Emax (%) 121 8.8 111 123 390 120 126 2600 85128 2400 88 129 39 96 130 460 96 133 1000 97 136 0.22 102 137 240 101138 22 94 139 31 103 140 390 92 141 460 95 142 4000 96 143 590 96 1441.0 104 145 810 106 146 2.5 100 147 10 100 148 0.053 103 149 25 100 15030 99 151 490 107 152 290 96 154 2400 94 155 1700 95 156 350 95 157 14091 158 1600 83 159 140 96 165 3800 80 167 2400 83 176 45 98 177 190 96179 0.31 100 180 17 106 181 240 89 182 2.3 92 183 40 94 184 9.3 93 18521 98 186 3300 86 187 370 93 188 23 97 189 78 88 191 2.9 107 192 150 108193 300 88 194 2400 81 195 250 102 196 30 104 197 100 90 198 56 92 20022 95 201 2000 92 202 19 97 204 710 102 207 26 110 208 940 93 209 190089 210 3600 86 211 1100 94 212 2200 89 213 0.44 102 214 1.5 105 215 2.5105 216 210 105 217 13 110 219 3000 91 221 1600 96 222 2100 102 223 1100110 224 1700 90 225 1000 98 226 2200 86 227 2400 102 228 2100 89 2291500 85 230 2600 80 233 5000 83 236 1800 86 237 490 90 238 2100 91 239280 102

TABLE 2-3 Ex. No. EC₅₀ (nM) Emax (%) 240 24 107 241 1.2 97 242 0.88 99243 17 97 244 2.6 97 245 2.0 97 246 730 113 247 960 102 249 0.61 99 2501.7 105 251 240 98 252 2900 93 254 88 105 255 8.1 102 257 2.6 97 2580.72 101 260 550 99 262 2500 94 263 57 88 264 21 91 265 2300 94 266 370095 267 3.4 94 268 1.5 103 269 3000 95 270 80 102 271 650 104 272 28 96274 260 118 275 3100 87 276 110 95 277 2.9 95 279 5.2 97 281 3300 81 2820.55 93 283 8.9 95 284 260 95 286 130 93 287 150 99 290 3300 79 291 2698 293 540 78 294 130 95 295 4.2 93 297 2100 76 298 280 92 299 95 90 3009.7 94 301 21 105 303 15 102 304 23 105 305 53 106 306 13 101 307 160098 308 590 109 309 3.1 106 310 2.2 101 311 3200 98 312 32 98 313 270 95315 170 103 316 330 91 318 1100 99 319 29 106 320 2000 74 321 2200 37322 25 71 323 96 95 324 8.0 95 325 5000 75 327 2600 86 328 7100 72 32922 93 331 1500 98 332 610 93 333 340 87 334 27 93 335 6.1 101 337 240088 338 490 83 339 11 101 340 2.5 109 341 13 103 342 30 104

Experimental Example 2-2 Measurement of Orexin Type 2 Receptor AgonistActivity

CHO cells forcibly expressing human OX2 receptor were seeded in eachwell of 384 well black transparent bottom plate (BD Falcon) at 7,500cells/well, and cultured for one day in a 5% CO₂ incubator at 37° C.After removal of the medium in the cell plate, assay buffer A containinga calcium indicator (HBSS (Life Technologies), 20 mM HEPES (LifeTechnologies), 0.1% BSA (Wako Pure Chemical Industries, Ltd.), 2.5 μg/mLFluo-4 AM (DOJINDO Chemical), 0.08% Pluronic F127 (DOJINDO Chemical),1.25 mM probenecid (DOJINDO Chemical)) was added at 30 μL/well. Theplate was stood for 30 min in a 5% CO₂ incubator at 37° C., and furtherstood at room temperature for 30 min. A test compound prepared bydiluting with assay buffer B (HBSS, 20 mM HEPES, 0.1% BSA) was added at10 μL/well, and the fluorescence value was measured by FDSSμCELL(Hamamatsu Photonics K.K.) every one sec for 1 min, and thereafter everytwo sec for 1 min 40 sec. The activity (%) of the test compound wascalculated assuming that variation in the fluorescence value when DMSOwas added instead of the test compound was 0% inhibition, and variationin the fluorescence value when OX-A was added at the final concentrationof 10 nM was 100% inhibition.

TABLE 2-4 Ex. No. EC₅₀ (nM) Emax (%) 343 150 109 344 290 109 345 21 105347 260 94 348 9.5 92 350 1600 116 353 1300 100 354 51 104 355 0.44 108356 21 98 357 84 101 359 1.1 97 360 210 98 362 390 95

Experimental Example 3 Measurement of Locomotor Activity in Mice

Increased locomotor activity is one of the indexes of arousal actiontogether with increase in wakefulness time, increase in bodytemperature, enhancement of cardiovascular system parameters and thelike. In this Experimental Example, the arousal action effective for thetreatment of narcolepsy was evaluated by measuring the locomotoractivity of mouse. Male C57BL/6J mice (6-10 weeks old, Japan CLEA) wereused for the measurement of locomotor activity (8 mice each group),infrared rays were irradiated from the top part of the cage, and alocomotor activity measuring device (MDC system—Neurosciences Idea)capable of quantifying the number of times the mice pass through theirradiated rays was used. To be specific, the mice were placed in thecage of the device and acclimatized for 4 hours or longer, and a testcompound was intraperitoneally administered (dose: 30 mg/kg bodyweight). The locomotor activity was measured for 2 hr after theadministration. In the test compound group, a solution obtained bydissolving the test compound in a solvent (composition: 10% DMSO, 10%Cremophor EL (trade name), 20% polyethylene glycol 400 (20% PEG400, 60%H₂O)) was administered to mice. On the other hand, in the control group,only the aforementioned solvent not containing the test compound wasadministered to mice.

The results are shown in Table 3 below.

TABLE 3 control Example test compound group Example 2 Example 5 340locomotor activity 372.00 ± 24.23 817.00 ± 67.88 1175.25 ± 61.97 979.25± 109.96 (counts) (mean ± S.E.M., n = 8)

As is clear from Table 3, the compound of the present invention enhancedthe locomotor activity of mice.

That is, the compound of the present invention has a waking-up effectand was shown to be effective for the treatment of narcolepsy.

Formulation Example 1 (Production of Capsule)

1) compound of Example 1 30 mg 2) crystalline cellulose 10 mg 3) lactose19 mg 4) magnesium stearate  1 mg total 60 mg

1), 2), 3) and 4) are mixed and filled in a gelatin capsule.

Formulation Example 2 (Production of Tablet)

1) compound of Example 1 30 g 2) lactose 50 g 3) cornstarch 15 g 4)calcium carboxymethylcellulose 44 g 5) magnesium stearate 1 g 1000tablets 140 g in total

The total amount of 1), 2), 3) and 30 g of 4) are kneaded with water,vacuum dried and sieved. The sieved powder is mixed with 14 g of 4) and1 g of 5), and the mixture is punched by a tableting machine. In thisway, 1000 tablets containing 30 mg of the compound of Example 1 pertablet are obtained.

INDUSTRIAL APPLICABILITY

The compound of the present invention has an orexin type 2 receptoragonist activity, and is useful as a prophylactic or therapeutic agentfor narcolepsy.

This application is based on patent application No. 2016-019834 filed inJapan, the contents of which are encompassed in full herein.

The invention claimed is:
 1. A pharmaceutical composition comprisingmethyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylateor a salt thereof.